Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV004789889 | SCV005398282 | pathogenic | Pseudohypoparathyroidism type I A | 2024-10-10 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. 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 (PMID: 29072892). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to alanine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0708 - Other missense variants comparable to the one identified in this case have conflicting previous evidence for pathogenicity. Two alternative changes have been reported. p.(Val159Glu) has been reported once as a VUS by a clinical laboratory in ClinVar. p.(Val159Met) has been reported in two individuals with GNAS-related features (PMIDs: 11788646, 23281139). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as de novo in two individuals with GNAS-related features (PMIDs: 21910239, 29620724). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |