Submissions for variant NM_000516.7(GNAS):c.569A>G (p.Tyr190Cys)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV003325148	SCV004030977	uncertain significance	not provided	2023-06-30	criteria provided, single submitter	clinical testing	Reported as c.572A>G p.(Tyr191Cys) in one family from a study screening for GNAS variants in 204 families with pseudohypoparathyroidism type 1A and pseudopseudohypoparathyroidism, but additional clinical information was not included (Snanoudj et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31886927)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003325148	SCV004376699	likely pathogenic	not provided	2022-10-20	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Tyr190 amino acid residue in GNAS. Other variant(s) that disrupt this residue have been observed in individuals with GNAS-related conditions (PMID: 8699958), which suggests that this may be a clinically significant amino acid residue. 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. This variant is also known as p.Tyr191Cys. This missense change has been observed in individual(s) with GNAS-related conditions (PMID: 31696922, 31886927). 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 tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 190 of the GNAS protein (p.Tyr190Cys).