Submissions for variant NM_000540.3(RYR1):c.2045G>A (p.Arg682Gln)

gnomAD frequency: 0.00002  dbSNP: rs372513400

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000721440	SCV000852507	uncertain significance	not provided	2018-01-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003591774	SCV004344390	likely pathogenic	RYR1-related disorder	2024-05-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 682 of the RYR1 protein (p.Arg682Gln). This variant is present in population databases (rs372513400, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive RYR1-related myopathy (PMID: 31127727, 34411415). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 590496). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg682 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been observed in individuals with RYR1-related conditions (PMID: 30611313, 35081925), which suggests that this may be a clinically significant amino acid residue. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005056477	SCV005727118	uncertain significance	not specified	2024-11-05	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.2045G>A (p.Arg682Gln) results in a conservative amino acid change located in the B30.2/SPRY domain of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.2045G>A has been reported in the literature in individuals affected with autosomal recessive RYR1-related myopathy and autosomal dominant malignant hyperthermia. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34411415, 33037202, 31127727). ClinVar contains an entry for this variant (Variation ID: 590496). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
GeneDx	RCV000721440	SCV005874757	likely pathogenic	not provided	2024-08-29	criteria provided, single submitter	clinical testing	Previously reported in the heterozygous state in a proband with congential myasthenia syndrome; a second RYR1 variant was not reported, and the R682Q variant was inherited from the unaffected mother (PMID: 31127727); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31127727, 34411415)