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| Dilated Cardiomyopathy v1.33 | MYZAP |
Zornitza Stark changed review comment from: 10 individuals from four unrelated families with bi-allelic variants in this gene with DCM. Supportive zebrafish model. Note the MYZAP and GCOM1 genes are part of the GRINL1A complex transcription unit. Some of the reported variants affect GCOM1 with postulated effect on MYZAP due to read through transcription (two families), and in the rest of the families MYZAP was affected directly. Sources: Literature; to: 10 individuals from four unrelated families with bi-allelic variants in this gene with DCM. Supportive zebrafish model. The MYZAP gene is part of the GRINL1A complex transcription unit (CTU), or GCOM1, which also includes the downstream POLR2M gene, or GRINL1A.. Some of the reported variants affect GCOM1 with postulated effect on MYZAP due to read through transcription (two families), and in the rest of the families MYZAP was affected directly. Transcription from an upstream promoter within the GRINL1A CTU produces 2 types of alternatively spliced transcripts: MYZAP transcripts, also called GRINL1A upstream (GUP) transcripts, which include only exons from the MYZAP gene, and GRINL1A combined (GCOM) transcripts, which include exons from both the MYZAP gene and the downstream POLR2M gene. Transcription of the POLR2M gene initiates at a downstream promoter within the GRINL1A CTU and produces alternatively spliced POLR2M transcripts, also called GRINL1A downstream (GDOWN) transcripts, which include only exons from the POLR2M gene Sources: Literature |
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| Dilated Cardiomyopathy v1.9 | DSG2 |
Zornitza Stark changed review comment from: Assessed as LIMITED by ClinGen for mono-allelic variants: Human genetic evidence supporting this gene-disease relationship includes one published definitive DCM case with truncating variant in DSG2 published by Garcia-Pavia et al (2011, PMID: 21859740). Of note, this person had limited ECG/arrhythmia phenotyping. Multiple other published variants have population frequencies which exclude them from scoring, as they are observed at a frequency higher than would be expected to have a pathogenic effect. In addition, this gene-disease association is supported by experimental evidence from postnatal DCM hearts showing reduced DSG2 signal in myocardium and other intercalated disc proteins were normal(Kessler et al, 2017, PMID: 28764973). In summary, there is limited evidence to support this gene-disease relationship. Bi-allelic variants: three families reported.; to: Assessed as LIMITED by ClinGen for mono-allelic variants: Human genetic evidence supporting this gene-disease relationship includes one published definitive DCM case with truncating variant in DSG2 published by Garcia-Pavia et al (2011, PMID: 21859740). Of note, this person had limited ECG/arrhythmia phenotyping. Multiple other published variants have population frequencies which exclude them from scoring, as they are observed at a frequency higher than would be expected to have a pathogenic effect. In addition, this gene-disease association is supported by experimental evidence from postnatal DCM hearts showing reduced DSG2 signal in myocardium and other intercalated disc proteins were normal(Kessler et al, 2017, PMID: 28764973). In summary, there is limited evidence to support this gene-disease relationship. Bi-allelic variants: three families reported, two with missense variants. DEFINITIVE for ARVC. |
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| Dilated Cardiomyopathy v1.9 | DSG2 |
Zornitza Stark changed review comment from: Assessed as LIMITED by ClinGen for mono-allelic variants: Human genetic evidence supporting this gene-disease relationship includes one published definitive DCM case with truncating variant in DSG2 published by Garcia-Pavia et al (2011, PMID: 21859740). Of note, this person had limited ECG/arrhythmia phenotyping. Multiple other published variants have population frequencies which exclude them from scoring, as they are observed at a frequency higher than would be expected to have a pathogenic effect. In addition, this gene-disease association is supported by experimental evidence from postnatal DCM hearts showing reduced DSG2 signal in myocardium and other intercalated disc proteins were normal(Kessler et al, 2017, PMID: 28764973). In summary, there is limited evidence to support this gene-disease relationship. Bi-allelic variants: two families reported.; to: Assessed as LIMITED by ClinGen for mono-allelic variants: Human genetic evidence supporting this gene-disease relationship includes one published definitive DCM case with truncating variant in DSG2 published by Garcia-Pavia et al (2011, PMID: 21859740). Of note, this person had limited ECG/arrhythmia phenotyping. Multiple other published variants have population frequencies which exclude them from scoring, as they are observed at a frequency higher than would be expected to have a pathogenic effect. In addition, this gene-disease association is supported by experimental evidence from postnatal DCM hearts showing reduced DSG2 signal in myocardium and other intercalated disc proteins were normal(Kessler et al, 2017, PMID: 28764973). In summary, there is limited evidence to support this gene-disease relationship. Bi-allelic variants: three families reported. |
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| Dilated Cardiomyopathy v1.5 | NEBL |
Bryony Thompson Added comment: Comment on list classification: Limited gene-disease vailidity, Classification - 09/25/2020 by ClinGen Dilated Cardiomyopathy GCEP. Evidence Summary: NEBL was evaluated for autosomal dominant dilated cardiomyopathy (DCM). Human genetic evidence supporting this gene-disease relationship includes case-level data. Arimura and colleagues (2000, PMID: 11140941) analyzed 83 DCM patients and 311 healthy controls, identifying 4 missense variants of unknown significance (VUSs) in 4 DCM cases. High minor allele frequencies (MAFs) and lack of segregation excluded these variants as evidence. Purevjav and colleagues (2010, PMID: 20951326) investigated a total of 260 DCM patients and 300 unrelated ethnic matched controls by direct DNA sequencing. Authors identified 4 missense VUSs. One of these variants (Q128R) was downgraded in level of evidence due to the lack of segregation. The other 3 variants were not scored because of their MAF. Perrot and colleagues (2016, PMID: 27186169) investigated a total of 389 patients with DCM, HCM, or LVNC, 320 Caucasian sex-matched controls and 192 Caucasian sex-matched blood donors and identified 3 missense VUSs in 4 families. One of these variants was also carried by healthy relatives and therefore was excluded, however this may be explained by reduced penetrance. The 2 other variants lacked segregation as well and therefore were also excluded. In addition, this gene-disease association is supported by animal models. Mastronotaro and colleagues (2015, PMID: 25987543) created a NEBL knockout mice that exhibited normal cardiac function up to 9 months of age but after 2 weeks of transaortic constriction (TAC), these mice showed Z-line widening since the age of 5 months and upregulation of cardiac stress genes (basal and after TAC) However, absence of clinical DCM features in KO-NEBL mice as well as Western Blot analysis which contradicted previous findings by showing a similar protein expression between knockout and wild-type mice, excluding it as evidence. Purevjav and colleagues (2010, PMID: 20951326) generated a transgenic mouse overexpressing WT or mutant NEBL under the control of the α-MyHC promoter (4 variants were tested). Mice overexpressing p.K60N or p.Q128R variants died within 1 year because of severe heart enlargement and heart failure. Mice overexpressing p.G202R or p.A592E were born and developed normally but after 6 months displayed reduced stress tolerance, cardiac enlargement due to left ventricle dilation, myocyte disarray, and interstitial cell infiltration. In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support the relationship of NEBL and autosomal dominant DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on October 11, 2019 (SOP Version 7). Gene Clinical Validity Standard Operating Procedures (SOP) - SOP7 |
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| Dilated Cardiomyopathy v0.110 | DES | Zornitza Stark Marked gene: DES as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated Cardiomyopathy v0.110 | DES | Zornitza Stark Gene: des has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated Cardiomyopathy v0.110 | DES | Zornitza Stark Phenotypes for gene: DES were changed from to Cardiomyopathy, dilated, 1I, MIM# 604765; MONDO:0011482 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated Cardiomyopathy v0.109 | DES | Zornitza Stark Publications for gene: DES were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated Cardiomyopathy v0.108 | DES | Zornitza Stark Mode of inheritance for gene: DES was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated Cardiomyopathy v0.107 | DES | Zornitza Stark reviewed gene: DES: Rating: GREEN; Mode of pathogenicity: None; Publications: 10430757, 11728149, 17325244, 23300193, 31514951, 26724190, 23349452, 25557463, 33947203; Phenotypes: Cardiomyopathy, dilated, 1I, MIM# 604765, MONDO:0011482; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dilated Cardiomyopathy v0.55 | PRDM16 |
Naomi Baker gene: PRDM16 was added gene: PRDM16 was added to Dilated Cardiomyopathy. Sources: Literature Mode of inheritance for gene: PRDM16 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PRDM16 were set to PMID: 23768516; 24387995; 31965688. Phenotypes for gene: PRDM16 were set to Cardiomyopathy, dilated, 1LL MIM#615373; Left ventricular noncompaction 8 MIM#615373 Review for gene: PRDM16 was set to AMBER Added comment: Arndt et al., 2013 (PMID:23768516) identified a minimal deletion region of PRDM16 in 1p36del syndrome. Resequencing a cohort of 75 LVNC patients identified three SNV mutations (one truncation, one frameshift, one missense) and sequencing a series of cardiac biopsies from 131 individuals with DCM identified 5 individuals with 4 previously unreported nonsynonomous variants. This publication was refuted by Leeuw & Houge 2014 (PMID: 24387995). Deplancq et al., 2020 (PMID: 31965688) describes the first fetal case of left ventricular non‐compaction (LVNC) with a heterozygous de novo nonsense variant. Sources: Literature |
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| Dilated Cardiomyopathy v0.55 | FLNC |
Paul De Fazio changed review comment from: PMID 32112656 summarises the mutational spectrum of FLNC. 60 different LoF and 3 different missense variants have been described across the literature and LOVD in patients/families with DCM. Other cardiac phenotypes (e.g. HCM) are also associated with variants in FLNC, but have a might higher incidence of missense variants over LoF variants. Knockdown in the zebrafish ortholog results in abnormal cardiac function and ultrastructure. Green on PanelApp GEL. Sources: Literature; to: PMID 32112656 summarises the mutational spectrum of FLNC. 60 different LoF and 3 different missense variants have been described across the literature and LOVD in patients/families with DCM. Other cardiac phenotypes (e.g. HCM) are also associated with variants in FLNC, but have a much higher incidence of missense variants over LoF variants. Knockdown in the zebrafish ortholog results in abnormal cardiac function and ultrastructure. Green on PanelApp GEL. Sources: Literature |
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| Dilated Cardiomyopathy v0.55 | FLNC |
Paul De Fazio gene: FLNC was added gene: FLNC was added to Dilated Cardiomyopathy. Sources: Literature Mode of inheritance for gene: FLNC was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: FLNC were set to 30067491; 28008423; 31245841; 28436997; 32112656 Phenotypes for gene: FLNC were set to Dilated cardiomyopathy Review for gene: FLNC was set to GREEN gene: FLNC was marked as current diagnostic Added comment: PMID 32112656 summarises the mutational spectrum of FLNC. 60 different LoF and 3 different missense variants have been described across the literature and LOVD in patients/families with DCM. Other cardiac phenotypes (e.g. HCM) are also associated with variants in FLNC, but have a might higher incidence of missense variants over LoF variants. Knockdown in the zebrafish ortholog results in abnormal cardiac function and ultrastructure. Green on PanelApp GEL. Sources: Literature |
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| Dilated Cardiomyopathy v0.55 | FKTN |
Paul De Fazio gene: FKTN was added gene: FKTN was added to Dilated Cardiomyopathy. Sources: Literature Mode of inheritance for gene: FKTN was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FKTN were set to 17036286; 19015585 Phenotypes for gene: FKTN were set to Cardiomyopathy, dilated, 1X MIM#611615 Review for gene: FKTN was set to AMBER gene: FKTN was marked as current diagnostic Added comment: Total 6 families (5 Japanese) with DCM and mild proximal muscle weakness. PMID 17036286: 4 Japanese families with dilated cardiomyopathy with no or minimal limb girdle muscle involvement and normal intelligence. The patients were chet for a 3kb retrotransposon in the FKTN 3' UTR (all patients) and a missense variant (either Gln358Pro or Arg179Thr, both absent from gnomAD). The 3kb insertion is associated with a common founder haplotype and is found in 87% of alleles causing autosomal recessive Fukuyama congenital muscular dystrophy. PMID 19015585: 1 patient with DCM, mild muscle involvement, and no brain involvement was chet for the 3kb insertion described above and Cys101Phe (absent from gnomad). The 3kb insertion was also found heterozygous in 2 other DCM patients and 3 controls. DOI: 10.1055/s-0036-1583659 (no PMID, only abstract available) describes 2 sibs of a consanguineous Turkish family with homozygous exon 3 deletion, who had mild, non-progressive proximal muscle weakness and DCM. Sources: Literature |
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| Dilated Cardiomyopathy v0.43 | DOLK |
Paul De Fazio gene: DOLK was added gene: DOLK was added to Dilated Cardiomyopathy. Sources: Literature Mode of inheritance for gene: DOLK was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DOLK were set to 31741824; 28816422; 24144945; 22242004 Phenotypes for gene: DOLK were set to Congenital disorder of glycosylation, type Im MIM#610768 Review for gene: DOLK was set to AMBER gene: DOLK was marked as current diagnostic Added comment: Not curated by ClinGen. This is a CDG gene. Patients may present with DCM (among other phenotypes). PMID 22242004 describes 11 young (5-13) patients with "predominantly nonsyndromic presentation of DCM". Sources: Literature |
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| Dilated Cardiomyopathy v0.31 | NEBL |
Zornitza Stark gene: NEBL was added gene: NEBL was added to Dilated Cardiomyopathy. Sources: Literature Mode of inheritance for gene: NEBL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NEBL were set to 27186169 Phenotypes for gene: NEBL were set to Hypertrophic cardiomyopathy; dilated cardiomyopathy Review for gene: NEBL was set to GREEN Added comment: 7 patients from 6 unrelated families described with missense variants in this gene; some with HOCM, some with DCM. Sources: Literature |
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| Dilated Cardiomyopathy v0.0 | DES |
Zornitza Stark gene: DES was added gene: DES was added to Dilated cardiomyopathy_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: DES was set to Unknown |
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