Submissions for variant NM_000540.3(RYR1):c.14717C>T (p.Ala4906Val)

dbSNP: rs118192153

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513729	SCV003443242	likely pathogenic	RYR1-related disorder	2022-07-04	criteria provided, single submitter	clinical testing	This missense change has been observed in individuals with clinical features of central core disease (PMID: 11741831; Invitae). This variant has been reported in individual(s) with clinical features of congenital fiber type disproportion (PMID: 30611313); however, the role of the variant in this condition is currently unclear. This variant is present in population databases (rs118192153, gnomAD 0.007%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 4906 of the RYR1 protein (p.Ala4906Val). This variant is also known as A4905V. 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. Experimental studies have shown that this missense change affects RYR1 function (PMID: 12642598). 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: 65926).
GeneDx	RCV000119555	SCV005324909	likely pathogenic	not provided	2024-02-27	criteria provided, single submitter	clinical testing	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: 12642598, 23558838, 27147545, 25637381, 30611313, 33767344, 20681998, 11741831)
GeneReviews	RCV000056173	SCV000087261	pathologic	Central core myopathy	2010-05-11	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Leiden Muscular Dystrophy (RYR1)	RCV000119555	SCV000154462	not provided	not provided		no assertion provided	not provided
CSER _CC_NCGL, University of Washington	RCV000056173	SCV000190571	uncertain significance	Central core myopathy	2014-06-01	no assertion criteria provided	research