Submissions for variant NM_000540.3(RYR1):c.929C>T (p.Ala310Val)

gnomAD frequency: 0.00001  dbSNP: rs966781989

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000487724	SCV000575160	uncertain significance	not provided	2017-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000487724	SCV000621640	uncertain significance	not provided	2017-10-18	criteria provided, single submitter	clinical testing	The A310V variant in the RYR1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The A310V variant is observed in 5/126,606 (0.0039%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). The A310V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret A310V as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001342781	SCV001536728	uncertain significance	RYR1-related disorder	2023-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 310 of the RYR1 protein (p.Ala310Val). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 425174). 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 with a negative predictive value of 95%. 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	RCV002496881	SCV002782405	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	2021-08-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004003413	SCV004820731	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-05-14	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 310 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 5/282580 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.