Submissions for variant NM_000540.3(RYR1):c.4729G>A (p.Ala1577Thr)

gnomAD frequency: 0.00003  dbSNP: rs118192120

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen	RCV004992001	SCV005619838	uncertain significance	RYR1-related myopathy	2024-08-27	reviewed by expert panel	curation	The c.4729G>A variant in RYR1 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 1577. The filtering allele frequency (the lower threshold of the 95% CI of 8/73780) of the c.4729G>A variant in RYR1 is 0.00006033 for African/African American chromosomes by gnomAD v4.1 (BA1, BS1, PM2 not met). The computational predictor REVEL gives a score of 0.908, which is above the threshold of 0.7, evidence that correlates with impact to RYR1 function (PP3). This variant has been reported in 2 probands with RYR1-related myopathy and has been detected in 1 individual with RYR1-related myopathy, compound heterozygous for the variant and a rare VUS, confirmed in trans by family testing (c.14818G>A (p.A4940T), SCV000852639.1). In summary, this variant meets the criteria to be classified as uncertain significance for RYR1-related myopathy with multiple patterns of inheritance reported, based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PP3. (ClinGen Congenital Myopathies VCEP specifications version 2; 08/27/2024)
PreventionGenetics, part of Exact Sciences	RCV000119622	SCV000852639	uncertain significance	not provided	2017-02-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000119622	SCV001986237	uncertain significance	not provided	2021-02-15	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed with a benign variant on the opposite allele (in trans) in a patient with congenital core myopathy in published published literature (Zhou et al., 2006); This variant is associated with the following publications: (PMID: 20301565, 17365175, 16940308)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854159	SCV002175384	uncertain significance	RYR1-related disorder	2024-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1577 of the RYR1 protein (p.Ala1577Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with congenital myopathy (PMID: 16940308). ClinVar contains an entry for this variant (Variation ID: 65923). 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 RYR1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect RYR1 function (PMID: 16940308). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002477185	SCV002788962	uncertain significance	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2022-04-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996483	SCV004820841	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1577 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotype(s) (ClinVar variation ID: 65923). This variant has been identified in 3/198252 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.
GeneReviews	RCV000056170	SCV000087258	pathologic	Central core myopathy	2010-05-11	no assertion criteria provided	curation	Converted during submission to Pathogenic.
RYR1 database	RCV000119622	SCV000154529	not provided	not provided		no assertion provided	not provided