Submissions for variant NM_000540.3(RYR1):c.3166G>C (p.Asp1056His)

dbSNP: rs2145447772

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen	RCV001580393	SCV001810076	likely pathogenic	Malignant hyperthermia of anesthesia	2023-04-07	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 aspartic acid with histidine at codon 1056 of the RYR1 protein, p.Asp1056His. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in two unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, both of these individuals had 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), PS4_Moderate (PMID:30236257). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. This variant segregates with MHS in two families with a total of fourteen informative meioses, PP1_Strong (PMID:24013571, The UK (Leeds) MH Unit). A REVEL score of 0.824 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Likely Pathogenic. Criteria implemented: PS4_Moderate, PP1_Strong.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001866101	SCV002144049	pathogenic	RYR1-related disorder	2021-10-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp1056 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been observed in individuals with RYR1-related conditions (PMID: 20681998), which suggests that this may be a clinically significant amino acid residue. 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 expected to disrupt RYR1 protein function. ClinVar contains an entry for this variant (Variation ID: 1210300). This missense change has been observed in individual(s) with malignant hyperthermia (PMID: 24013571, 30236257). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 1056 of the RYR1 protein (p.Asp1056His).