Submissions for variant NM_000540.3(RYR1):c.13927G>A (p.Ala4643Thr)

gnomAD frequency: 0.00008  dbSNP: rs200286252

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001352513	SCV001547071	uncertain significance	RYR1-related disorder	2022-08-31	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 4643 of the RYR1 protein (p.Ala4643Thr). 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 autosomal dominant congenital muscular dystrophy (PMID: 29172004). This variant is also known as p.Ala4636Thr. ClinVar contains an entry for this variant (Variation ID: 1047755). 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 not expected to disrupt RYR1 protein function. This variant disrupts the p.Ala4643 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27159402). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
CeGaT Center for Human Genetics Tuebingen	RCV002264278	SCV002543921	uncertain significance	not provided	2022-06-01	criteria provided, single submitter	clinical testing	RYR1: PS1:Moderate, PP3
3billion	RCV002283542	SCV002573112	uncertain significance	Central core myopathy	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.008%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.53; 3Cnet: 0.80). Same nucleotide change resulting in same amino acid change (PMID: 29172004 ) and a different missense change at the same codon (p.Ala4643Pro/ PMID: 27159402 ) have been previously reported to be associated with RYR1-related disorder. However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV002486466	SCV002781497	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	2021-10-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001352513	SCV004123276	uncertain significance	RYR1-related disorder	2023-06-08	criteria provided, single submitter	clinical testing	The RYR1 c.13927G>A, p.(Ala4643Thr) missense variant has been reported in a heterozygous state in one individual with myopathy (PMID: 29172004). A different amino acid substitution at the same codon, p.Ala4643Pro, has been reported in a heterozygous state in an individual with RYR1-related myopathy (PMID: 27159402). This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. This variant has been classified as a variant of uncertain significance by multiple submitters in ClinVar, including one submission in which the variant was identified in a homozygous state in an individual with myopathy (VCV001047755.8). Based on the available evidence, the c.13927G>A, p.(Ala4643Thr) variant is classified as a variant of uncertain significance for RYR1-related disorders.
All of Us Research Program, National Institutes of Health	RCV004005249	SCV004816253	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 4643 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 RYR1-related disorders in the literature. This variant has been identified in 20/251480 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.