Submissions for variant NM_000540.3(RYR1):c.3301G>A (p.Val1101Met)

gnomAD frequency: 0.00001  dbSNP: rs145088074

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182605	SCV000234964	uncertain significance	not provided	2023-08-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Identified in a patient with congenital fiber-type disproportion who also harbored a second RYR1 variant on the opposite allele (Cummings et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35428369, 28424332)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000785928	SCV000924507	likely pathogenic	Central core myopathy	2018-06-15	criteria provided, single submitter	research	The heterozygous p.Val1101Met variant was identified by our study in the compound heterozygous state, along with another likely pathogenic variant, in one individual with central core disease. This variant has been identified in <0.01% (1/34420) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs145088074). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The Valine (Val) at position 1101 is highly conserved in mammals and evolutionarily distant species, raising the possibility that a change at this position may not be tolerated. Computational tools do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its pathogenicity, this variant is likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852321	SCV002234615	pathogenic	RYR1-related disorder	2023-12-25	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1101 of the RYR1 protein (p.Val1101Met). This variant is present in population databases (rs145088074, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of autosomal recessive RYR1-related conditions (PMID: 2842332; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as chr19:38958372G>A. ClinVar contains an entry for this variant (Variation ID: 201148). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. For these reasons, this variant has been classified as Pathogenic.
All of Us Research Program, National Institutes of Health	RCV003996724	SCV004820808	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 1101 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: 201148). This variant has been identified in 3/282824 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.