Submissions for variant NM_000540.3(RYR1):c.3527C>T (p.Thr1176Ile)

dbSNP: rs549201486

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001580395	SCV001810079	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 tyrosine with isoleucine at codon 1176 of the RYR1 protein, p.(Tyr1176Ile). The maximum allele frequency for this variant among the six major gnomAD populations is SAS: 0.0005879, 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 SAS 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 <0.5 (0.162) supports a benign status for this variant, BP4. This variant has been classified as a Variant of Uncertain Significance. Criteria implemented: BP4.
PreventionGenetics, part of Exact Sciences	RCV000721500	SCV000852577	uncertain significance	not provided	2016-07-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002060957	SCV002468100	likely benign	RYR1-related disorder	2024-12-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004702372	SCV005205087	uncertain significance	not specified	2024-06-06	criteria provided, single submitter	clinical testing	Variant summary: RYR1 c.3527C>T (p.Thr1176Ile) results in a non-conservative amino acid change located in the B30.2/SPRY domain (IPR001870) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251478 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RYR1 causing Malignant Hyperthermia Susceptibility (7.6e-05 vs 8.8e-05), allowing no conclusion about variant significance. c.3527C>T has been reported in the literature in at least one family affected with Malignant Hyperthermia Susceptibility (e.g. Miller_BJA_2018). This report does not provide unequivocal conclusions about association of the variant with Malignant Hyperthermia Susceptibility. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35849058, 30236257). ClinVar contains an entry for this variant (Variation ID: 590517). Based on the evidence outlined above, the variant was classified as uncertain significance.