Submissions for variant NM_000540.3(RYR1):c.13892A>C (p.Tyr4631Ser)

dbSNP: rs1568593922

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000808855	SCV000948980	pathogenic	RYR1-related disorder	2022-09-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr4631 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been observed in individuals with RYR1-related conditions (PMID: 16621918, 21911697, 28357410), 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 RYR1 protein function. ClinVar contains an entry for this variant (Variation ID: 653142). This missense change has been observed in individual(s) with congenital myopathy (Invitae). 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 serine, which is neutral and polar, at codon 4631 of the RYR1 protein (p.Tyr4631Ser).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002537300	SCV003761224	likely pathogenic	RYR1-related myopathy	2023-01-25	criteria provided, single submitter	curation	The heterozygous p.Tyr4631Ser variant in RYR1 was identified by our study in one individual with central core myopathy. Trio exome analysis showed this variant to be de novo. The p.Tyr4631Ser variant in RYR1 has not been previously reported in the literature in individuals with RYR1-associated disease. This variant has been reported in ClinVar (Variation ID:653142) and has been interpreted as pathogenic by Invitae. This variant is absent from population databases. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for RYR1-associated myopathy. ACMG/AMP Criteria applied: PS2, PM2_Supporting, PP3 (Richards 2015).
Laboratorio de Biologia Molecular - Genetica, Hospital de Pediatria Garrahan	RCV002537300	SCV004242338	pathogenic	RYR1-related myopathy	2024-02-05	criteria provided, single submitter	clinical testing	The heterozygous c.13892A>C p.(Tyr4631Ser) variant in RYR1 was identified in a patient with central core myopathy. The variant was not detected in the mother, and the father was not available. This variant has been previously reported by the Broad Institute Rare Disease Group in a patient with central core myopathy (de novo variant, classified as Likely Pathogenic). Additionally, Invitae has reported this variant (observed to be de novo in at least one individual) and interpreted it as pathogenic. The variant is absent from population databases. In silico analysis suggests that this variant disrupts RYR1 protein function. For these reasons, this variant has been classified as Pathogenic.