Submissions for variant NM_000540.3(RYR1):c.3043C>T (p.Arg1015Cys)

gnomAD frequency: 0.00004  dbSNP: rs139006437

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000655543	SCV000777474	uncertain significance	RYR1-related disorder	2022-08-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1015 of the RYR1 protein (p.Arg1015Cys). This variant is present in population databases (rs139006437, gnomAD 0.02%). 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: 544410). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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	RCV002485486	SCV002785180	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
Revvity Omics, Revvity	RCV003140047	SCV003827496	uncertain significance	not provided	2020-09-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004004144	SCV004821641	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1015 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.6 < inconclusive < 0.85, 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 12/279094 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.
GeneDx	RCV003140047	SCV005078894	uncertain significance	not provided	2023-11-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
GenomeConnect - Invitae Patient Insights Network	RCV003330872	SCV004037574	not provided	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital myopathy with fiber type disproportion; Multiminicore myopathy		no assertion provided	phenotyping only	Variant classified as Uncertain significance and reported on 03-15-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.