Submissions for variant NM_000516.7(GNAS):c.691C>T (p.Arg231Cys)

dbSNP: rs1601162438

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Medicine Lab, University of California San Francisco	RCV001007922	SCV001167633	pathogenic	Pseudohypoparathyroidism	2019-01-31	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001007922	SCV001429316	pathogenic	Pseudohypoparathyroidism	2019-02-28	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269956	SCV001450336	likely pathogenic	not provided	2017-01-25	criteria provided, single submitter	clinical testing
GeneDx	RCV001269956	SCV001817386	pathogenic	not provided	2019-11-13	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31886927, 18812479, 18796523, 26701869, 30349702, 11600516, 25044890)
Invitae	RCV001269956	SCV002217325	pathogenic	not provided	2023-05-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt GNAS protein function. ClinVar contains an entry for this variant (Variation ID: 816910). This missense change has been observed in individual(s) with pseudohypoparathyroidism Ia and/or pseudopseudohypoparathyroidism (PMID: 11600516, 25044890, 30349702). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 231 of the GNAS protein (p.Arg231Cys).
3billion	RCV002283517	SCV002573121	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. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.86; 3Cnet: 0.90). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000816910). A different missense change at the same codon (p.Arg231His) has been reported to be associated with GNAS-related disorder (ClinVar ID: VCV000015946 / PMID: 8702665). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV002497329	SCV002810970	pathogenic	McCune-Albright syndrome; Pseudohypoparathyroidism type 1C; Pseudohypoparathyroidism type 1B; Pseudopseudohypoparathyroidism; Progressive osseous heteroplasia; Pituitary adenoma 3, multiple types; ACTH-independent macronodular adrenal hyperplasia 1; Pseudohypoparathyroidism type I A	2022-03-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002549273	SCV003529957	pathogenic	Inborn genetic diseases	2021-06-04	criteria provided, single submitter	clinical testing	The c.691C>T (p.R231C) alteration is located in exon 9 (coding exon 9) of the GNAS gene. This alteration results from a C to T substitution at nucleotide position 691, causing the arginine (R) at amino acid position 231 to be replaced by a cysteine (C). Based on data from the Genome Aggregation Database (gnomAD), the GNAS c.691C>T alteration was not observed, with coverage at this position. This alteration was reported de novo in two patients with phenotypes consistent with Albright hereditary osteodystrophy (AHO) and pseudohypoparathyroidism type 1a (PHP-1a)/pseudopseudohypoparathyroidism (PPHP) (Freson, 2008; Leclercq, 2018). Another patient with this alteration had AHO and PPHP and was found to have 58% Gsα protein activity (Ahrens, 2001). In addition, an alteration affecting the same amino acid, p.R231H, was reported in a mother and her two children with AHO/PHP-1a (Farfel, 1996). This amino acid position is highly conserved in available vertebrate species. The p.R231C alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Revvity Omics, Revvity	RCV001269956	SCV003829966	likely pathogenic	not provided	2021-12-13	criteria provided, single submitter	clinical testing
New York Genome Center	RCV003336225	SCV004046480	likely pathogenic	Pseudohypoparathyroidism type 1C; Pseudohypoparathyroidism type 1B; Pseudopseudohypoparathyroidism; Pseudohypoparathyroidism type I A	2023-02-03	criteria provided, single submitter	clinical testing	The c.691C>T, p.(Arg231Cys) variant identified in the GNAS gene substitutes a well conserved Arginine for Cysteine at amino acid 231/395 (exon 9/13). This variant is absent from population databases. (gnomADv2.1.1, gnomADv3.1.2, BRAVO-TOPMed, All of Us) suggesting it is not a common benign variant in the populations represented in those databases. In silico algorithms predict this variant to be damaging to the function of the canonical protein (REVEL: 0.857). The c.691C>T, p.(Arg231Cys) is reported in ClinVar in Pathogenic/Likely Pathogenic (VarID:816910; two stars, 7 submissions, no conflicts), and a different amino acid change at the same amino acid is also reported as Pathogenic (p.Arg231His; VarID:15946). This variant has been reported in individuals in the literature with pseudohypoparathyroidism or pseudopseudohypoparathyroidism [PMID:11600516, 25044890], and in an infant with Albright hereditary osteodystrophy [PMID: 30349702]. Given its absence in population databases, in silico prediction of a damaging effect on protein function, and observation in several individuals in the literature, the c.691C>T, p.(Arg231Cys) variant identified in the GNAS gene is reported as Likely Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004536045	SCV004120551	pathogenic	GNAS-related disorder	2023-06-07	criteria provided, single submitter	clinical testing	The GNAS c.691C>T variant is predicted to result in the amino acid substitution p.Arg231Cys. This variant has not been found in the general population. It has been reported in patients with pseudo-pseudohypoparathyroidism (PPHP) or acrosyphodysplasia (Ahrens et al. 2001, PMID: 11600516; Mitsui et al. 2014, PMID: 25044890). Of note, a different change at the same codon (c.692G>A, p.Arg231His) has been reported to be pathogenic for pseudohypoparathyroidism type Ia (PHP-Ia) due to a disturbance of the interaction between the switch 2 and 3 regions of Gsa (Farfel et al. 1996, PMID: 8702665). This variant is interpreted as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV002283517	SCV004242453	pathogenic	Pseudohypoparathyroidism type I A	2019-02-28	criteria provided, single submitter	clinical testing	Criteria applied: PS4, PS2_MOD, PM5, PM2_SUP, PP2,PP3