Submissions for variant NM_000540.3(RYR1):c.3442G>A (p.Val1148Ile)

gnomAD frequency: 0.00005  dbSNP: rs201174268

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000721497	SCV000852573	uncertain significance	not provided	2013-10-21	criteria provided, single submitter	clinical testing
Invitae	RCV000817122	SCV000957667	uncertain significance	RYR1-related disorder	2022-07-12	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1148 of the RYR1 protein (p.Val1148Ile). This variant is present in population databases (rs201174268, gnomAD 0.009%). 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: 590515). 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. 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249075	SCV001423026	uncertain significance	not specified	2020-01-22	criteria provided, single submitter	curation	The p.Val1148Ile variant in RYR1 has not been previously reported in individuals with RYR1-related diseases in the literature and has been identified in 0.008516% (11/129176) of European (non-Finnish) chromosomes and 0.008516% (3/35438) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201174268). Please note that RYR1-related diseases have been associated with both dominant and recessive inheritance. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Val1148Ile variant is uncertain. ACMG/AMP Criteria applied: BP4 (Richards 2015).
GeneDx	RCV000721497	SCV001823369	uncertain significance	not provided	2022-04-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics	RCV002499327	SCV002812265	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	2021-08-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002535005	SCV003722525	uncertain significance	Inborn genetic diseases	2021-09-17	criteria provided, single submitter	clinical testing	The c.3442G>A (p.V1148I) alteration is located in exon 26 (coding exon 26) of the RYR1 gene. This alteration results from a G to A substitution at nucleotide position 3442, causing the valine (V) at amino acid position 1148 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000721497	SCV003810546	uncertain significance	not provided	2021-05-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003999839	SCV004815225	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1148 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 16/282862 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.