Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV004788497 | SCV005398084 | uncertain significance | Pseudohypoparathyroidism type I A | 2024-09-23 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Loss-of-function has been associated with the hypoparathyroidism phenotypes (PMID: 10980525), while gain-of-function has been reported for somatic variants in cancers (PMID: 11588148). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0113 - This gene is known to be imprinted (OMIM; PMID: 10980525). (I) 0115 - Variants in this gene are known to have variable expressivity. Although some probands diagnosed with a disorder of GNAS inactivation have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in other family members (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to alanine. (I) 0219 - This variant is non-coding in an alternative transcript. It is coding in transcripts that encode the G-alpha domain which contains a cluster of pathogenic variants commonly associated with PhP-Ia, Ic, PPHP and POH/OC (UCSC, DECIPHER, PMID: 25851935). Of the transcripts in which it is coding, the NM_000516, known as Gs alpha, is biallelically expressed, except tissues such as thyroid and pituitary glands in which the maternal allele is expressed (NCBI, UCSC). In addition, it is also coding in NM_001077488, which is biallelically expressed, and in NM_080425, which is paternally expressed (NCBI, UCSC). (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional G-alpha domain (NCBI, DECIPHER). This residue is annotated as part of the conserved Walker A motif as well as of the GoLoco binding site motif (NCBI). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0906 - Segregation evidence for this variant is inconclusive. Some unaffected relatives were found to have the variant; however, there is high variable expressivity (PMIDs: 11784876, 29072892). Three other heterozygous relatives have features of GNAS-related disorders. 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by segregation analysis, father not tested), and the mother inherited it from her father. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |