Submissions for variant NM_000516.7(GNAS):c.772C>T (p.Arg258Trp)

dbSNP: rs137854535

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris	RCV000017306	SCV000586752	pathogenic	Pseudopseudohypoparathyroidism	2017-01-06	criteria provided, single submitter	clinical testing	Intellectual disability; small stature
Ambry Genetics	RCV001265731	SCV001443900	pathogenic	Inborn genetic diseases	2018-05-17	criteria provided, single submitter	clinical testing
Genetics of Obesity Study, University of Cambridge	RCV001731308	SCV001573818	pathogenic	Pseudohypoparathyroidism type I A	2020-06-01	criteria provided, single submitter	research
GeneDx	RCV000595336	SCV002007492	pathogenic	not provided	2023-09-22	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect as R258W causes a specific defect in activation (PMID: 9727013); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9727013, 28708303, 31886927, 36835474, 27535533, 34614324)
3billion	RCV001731308	SCV002572522	pathogenic	Pseudohypoparathyroidism type I A	2022-09-01	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.69; 3Cnet: 0.54). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000015941). A different missense change at the same codon (p.Arg258Gln) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000453009). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
CeGaT Center for Human Genetics Tuebingen	RCV000595336	SCV004150724	pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	GNAS: PM2, PM5, PS4:Moderate, PM6:Supporting, PP2, PP3, PS3:Supporting
Labcorp Genetics (formerly Invitae), Labcorp	RCV000595336	SCV004298111	pathogenic	not provided	2023-09-17	criteria provided, single submitter	clinical testing	This variant is also known as c.775C>T (p.Arg259Trp). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 258 of the GNAS protein (p.Arg258Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of GNAS-related conditions (PMID: 28708303, 31886927, 34614324). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 15941). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GNAS protein function. Experimental studies have shown that this missense change affects GNAS function (PMID: 9727013, 34614324). This variant disrupts the p.Arg258 amino acid residue in GNAS. Other variant(s) that disrupt this residue have been observed in individuals with GNAS-related conditions (PMID: 29095814, 34614324), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000017306	SCV000037578	pathogenic	Pseudopseudohypoparathyroidism	1998-09-11	no assertion criteria provided	literature only
Eurofins Ntd Llc (ga)	RCV000595336	SCV000702092	uncertain significance	not provided	2016-11-09	flagged submission	clinical testing