Submissions for variant NM_000540.3(RYR1):c.9635A>G (p.Glu3212Gly)

gnomAD frequency: 0.00038  dbSNP: rs199738299

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001801799	SCV002047644	uncertain significance	Malignant hyperthermia of anesthesia	2023-04-06	reviewed by expert panel	curation	This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of glutamic acid with glycine at codon 3212 of the RYR1 protein, p.(Glu3212Gly). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.0005609, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted) (PMID:30236257). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.624 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented.
Illumina Laboratory Services, Illumina	RCV000285479	SCV000412664	uncertain significance	Congenital multicore myopathy with external ophthalmoplegia	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000342818	SCV000412665	likely benign	Neuromuscular disease, congenital, with uniform type 1 fiber	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000391499	SCV000412666	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000288960	SCV000412667	likely benign	Central core myopathy	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000512826	SCV000534154	uncertain significance	not provided	2021-10-20	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 12668474)
CeGaT Center for Human Genetics Tuebingen	RCV000512826	SCV000608901	uncertain significance	not provided	2024-08-01	criteria provided, single submitter	clinical testing	RYR1: PM2
Labcorp Genetics (formerly Invitae), Labcorp	RCV000556213	SCV000660096	likely benign	RYR1-related disorder	2024-01-29	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198104	SCV001368905	uncertain significance	Congenital myopathy with fiber type disproportion	2019-03-12	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP2,PP3.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000391499	SCV001441079	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2019-01-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001820986	SCV002065945	uncertain significance	not specified	2018-05-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002495039	SCV002812259	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	2022-04-05	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000512826	SCV003810556	uncertain significance	not provided	2019-04-15	criteria provided, single submitter	clinical testing
3billion	RCV000285479	SCV003841782	uncertain significance	Congenital multicore myopathy with external ophthalmoplegia	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.028%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.62). Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV000391499	SCV004040642	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-01-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000391499	SCV004358173	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-05-09	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 3212 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 an individual affected with malignant hyperthermia susceptibility (PMID: 30236257). This variant has been identified in 58/203964 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.