Mendeliome
Gene: GNAS-AS1 Red List (low evidence)Red List (low evidence)
Single report of a AD-PHP-Ib kindred with a maternally inherited deletion limited to GNAS-AS1 (Chillambhi et al 2010). Further reports of maternally inherited deletions including regions of both GNAS-AS1 and exon NESP55. Although deletions in this region appear to be causative of AD-PHP-Ib, evidence for deletions limited to only GNAS-AS1 is limited to date.
Note, this non-coding RNA is paternally expressed, but causative deletions have been maternally inherited.
Reports of two AD-PHP-Ib kindreds with 4-kb microdeletions comprising the entire NESP55 DMR. These include exon NESP55 (GNAS encoded) and exons 3 and 4 of the GNAS antisense transcript. It remains unknown whether the observed imprinting changes and PTH resistance in these patients result from the loss of NESP55 expression or the loss of the deleted genomic region.
Chillambhi et al reported a AD-PHP-Ib kindred and identified a novel deletion that exclusively affects exons encoding the GNAS-AS. Overlapping with the previously identified deletions by approximately 1.5 kb. Unlike the previously identified deletions associated with AD-PHP-Ib, the novel deletion not only disrupts methylation of three GNAS DMRs (A/B, AS, and XL) after maternal transmission but also appears to partially alter methylation of the NESP55 and the A/B DMRs after paternal transmission, revealing a novel cis-acting mechanism that governs imprinting on both parental alleles.
Rezwan et al reported two further families with 33bp and 40bp deletions intronic to both NESP55 and NESP-AS. These were not definitively causative of the phenotype in the family.Created: 24 Oct 2021, 5:32 a.m. | Last Modified: 24 Oct 2021, 5:32 a.m.
Panel Version: 0.9439
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Phenotypes
Pseudohypoparathyroidism type 1b MIM no: 603233
Publications
Tag SV/CNV tag was added to gene: GNAS-AS1.
Gene: gnas-as1 has been classified as Red List (Low Evidence).
Phenotypes for gene: GNAS-AS1 were changed from to Pseudohypoparathyroidism type 1b MIM no: 603233
Publications for gene: GNAS-AS1 were set to
Mode of inheritance for gene: GNAS-AS1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, maternally imprinted (paternal allele expressed)
Gene: gnas-as1 has been classified as Red List (Low Evidence).
gene: GNAS-AS1 was added gene: GNAS-AS1 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: GNAS-AS1 was set to Unknown
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at panelapp@genomicsengland.co.uk
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.