Submissions for variant NM_000540.3(RYR1):c.4306G>A (p.Val1436Met)

gnomAD frequency: 0.00005  dbSNP: rs200289457

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000356178	SCV000412153	uncertain significance	Neuromuscular disease, congenital, with uniform type 1 fiber	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000275614	SCV000412154	uncertain significance	Central core myopathy	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000312053	SCV000412155	uncertain significance	Congenital multicore myopathy with external ophthalmoplegia	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000371141	SCV000412156	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV000513329	SCV000608897	uncertain significance	not provided	2024-11-01	criteria provided, single submitter	clinical testing	RYR1: PM2:Supporting, PP3
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526894	SCV000659939	likely benign	RYR1-related disorder	2025-01-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000513329	SCV001829558	uncertain significance	not provided	2020-11-12	criteria provided, single submitter	clinical testing	Reported in a family with malignant hyperthermia susceptibility (Heytens et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Ambry Genetics	RCV002523063	SCV003711593	uncertain significance	Inborn genetic diseases	2021-08-09	criteria provided, single submitter	clinical testing	The c.4306G>A (p.V1436M) alteration is located in exon 30 (coding exon 30) of the RYR1 gene. This alteration results from a G to A substitution at nucleotide position 4306, causing the valine (V) at amino acid position 1436 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000513329	SCV003813154	uncertain significance	not provided	2022-03-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000371141	SCV004820835	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2024-09-11	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 1436 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one family affected with malignant hyperthermia susceptibility in the literature. This variant has been identified in 13/282812 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.
PreventionGenetics, part of Exact Sciences	RCV000526894	SCV000852617	uncertain significance	RYR1-related disorder	2024-06-20	no assertion criteria provided	clinical testing	The RYR1 c.4306G>A variant is predicted to result in the amino acid substitution p.Val1436Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0085% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-38968362-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000513329	SCV001931543	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000513329	SCV001957951	uncertain significance	not provided		no assertion criteria provided	clinical testing