NM_000540.3(RYR1):c.7072A>C (p.Ile2358Leu) AND RYR1-related disorder

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 17, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002535010.2

Allele description [Variation Report for NM_000540.3(RYR1):c.7072A>C (p.Ile2358Leu)]

NM_000540.3(RYR1):c.7072A>C (p.Ile2358Leu)

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.7072A>C (p.Ile2358Leu)

HGVS:

NC_000019.10:g.38499679A>C
NG_008866.1:g.70980A>C
NM_000540.3:c.7072A>CMANE SELECT
NM_001042723.2:c.7072A>C
NP_000531.2:p.Ile2358Leu
NP_000531.2:p.Ile2358Leu
NP_001036188.1:p.Ile2358Leu
LRG_766t1:c.7072A>C
LRG_766:g.70980A>C
LRG_766p1:p.Ile2358Leu
NC_000019.9:g.38990319A>C
NM_000540.2:c.7072A>C

Protein change:

I2358L

Links:

dbSNP: rs759306349

NCBI 1000 Genomes Browser:

rs759306349

Molecular consequence:

NM_000540.3:c.7072A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.7072A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: RYR1-related disorder
Synonyms:: RYR1-Related Disorders; RYR1-related condition
Identifiers:: MedGen: CN239331

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003461854	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 17, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23558838, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003461854

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 17, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Ryanodine receptor type 1 gene variants in the malignant hyperthermia-susceptible population of the United States.

Brandom BW, Bina S, Wong CA, Wallace T, Visoiu M, Isackson PJ, Vladutiu GD, Sambuughin N, Muldoon SM.

Anesth Analg. 2013 May;116(5):1078-1086. doi: 10.1213/ANE.0b013e31828a71ff. Epub 2013 Apr 4.

PubMed [citation]

PMID:: 23558838
PMCID:: PMC3633164

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003461854.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces isoleucine with leucine at codon 2358 of the RYR1 protein (p.Ile2358Leu). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and leucine. This variant is present in population databases (rs759306349, ExAC 0.003%). This variant has been observed in individual(s) with clinical features of malignant hyperthermia (PMID: 23558838). ClinVar contains an entry for this variant (Variation ID: 590581). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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