Submissions for variant NM_000540.3(RYR1):c.13909A>G (p.Thr4637Ala)

dbSNP: rs118192166

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000119487	SCV000491288	likely pathogenic	not provided	2019-01-11	criteria provided, single submitter	clinical testing	The T4637A variant in the RYR1 gene has been reported previously in the heterozygous state in affected individuals of a family with congenital myopathy that showed clinical and histologic features of central core disease and nemaline myopathy (Scacheri et al., 2000). The T4637A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T4637A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in the same and nearby residues (E4634K, E4635Q, T4637I, G4638S, G4638D) have been reported in the Human Gene Mutation Database in association with RYR1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. The T4637A variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
PreventionGenetics, part of Exact Sciences	RCV000119487	SCV000852375	pathogenic	not provided	2016-03-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824568	SCV002074539	pathogenic	Malignant hyperthermia of anesthesia	2022-01-06	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.13909A>G (p.Thr4637Ala) results in a non-conservative amino acid change located in the Ryanodine Receptor TM 4-6 domain (IPR009460, residues 4383-4671) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251678 control chromosomes (gnomAD and publication data). c.13909A>G has been reported in the literature in multiple individuals with an autosomal dominant congenital myopathy that shows clinical and histologic features of both central core disease and nemaline rod myopathy and this variant co-segregated with the disease in one family (Scacheri_2000). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other variants (p.T4637I, P.T4637K) that disrupt the same residue have been found in affected individuals (PMID: 12565913, PMID: 33333461) and p.T4637I has been classified as pathogenic in ClinVar database, suggesting that the threonine residue is critical for RYR1 protein function. Additionally, other missense variants nearby this residue at the same domain were reported in patients with Central core disease/Myopathy in HGMD. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic and likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851836	SCV002148382	pathogenic	RYR1-related disorder	2023-09-06	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with autosomal dominant congenital myopathy (PMID: 11113224). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr4637 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12565913; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 12992). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 4637 of the RYR1 protein (p.Thr4637Ala).
OMIM	RCV000013864	SCV000034111	pathogenic	Central core myopathy	2000-12-12	no assertion criteria provided	literature only
RYR1 database	RCV000119487	SCV000154394	not provided	not provided		no assertion provided	not provided