ClinVar Miner

Submissions for variant NM_000516.7(GNAS):c.682C>A (p.Arg228Ser)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV005154588 SCV005781148 likely pathogenic not provided 2024-10-21 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 228 of the GNAS protein (p.Arg228Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pseudohypoparathyroidism or pseudopseudohypoparathyroidism (PMID: 31886927). This variant is also known as c.685C>A (p.Arg229Ser). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GNAS protein function with a positive predictive value of 95%. This variant disrupts the p.Arg228 amino acid residue in GNAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24914079, 34614324). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

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