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NM_000540.3(RYR1):c.2645C>T (p.Ala882Val) AND Malignant hyperthermia, susceptibility to, 1

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Feb 5, 2024
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001124721.13

Allele description [Variation Report for NM_000540.3(RYR1):c.2645C>T (p.Ala882Val)]

NM_000540.3(RYR1):c.2645C>T (p.Ala882Val)

Gene:
RYR1:ryanodine receptor 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
19q13.2
Genomic location:
Preferred name:
NM_000540.3(RYR1):c.2645C>T (p.Ala882Val)
HGVS:
  • NC_000019.10:g.38463490C>T
  • NG_008866.1:g.34791C>T
  • NM_000540.3:c.2645C>TMANE SELECT
  • NM_001042723.2:c.2645C>T
  • NP_000531.2:p.Ala882Val
  • NP_000531.2:p.Ala882Val
  • NP_001036188.1:p.Ala882Val
  • LRG_766t1:c.2645C>T
  • LRG_766:g.34791C>T
  • LRG_766p1:p.Ala882Val
  • NC_000019.9:g.38954130C>T
  • NM_000540.2:c.2645C>T
Protein change:
A882V
Links:
dbSNP: rs143701391
NCBI 1000 Genomes Browser:
rs143701391
Molecular consequence:
  • NM_000540.3:c.2645C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042723.2:c.2645C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
62

Condition(s)

Name:
Malignant hyperthermia, susceptibility to, 1 (MHS1)
Synonyms:
Anesthesia related hyperthermia; Malignant hyperpyrexia; Fulminating hyperpyrexia; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007783; MedGen: C2930980; Orphanet: 423; OMIM: 145600

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001283706Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)
Uncertain significance
(Jan 13, 2018)
germlineclinical testing

Citation Link,

SCV004820779All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain Significance
(Feb 5, 2024)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown62not providednot provided108544not providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001283706.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From All of Us Research Program, National Institutes of Health, SCV004820779.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided62not providednot providedclinical testing PubMed (1)

Description

This missense variant replaces alanine with valine at codon 882 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 not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 41/281414 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided62not providednot providednot provided

Last Updated: Nov 3, 2024