NM_000540.3(RYR1):c.3495C>T (p.Gly1165=) AND Malignant hyperthermia, susceptibility to, 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 27, 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:: RCV003514402.5

Allele description [Variation Report for NM_000540.3(RYR1):c.3495C>T (p.Gly1165=)]

NM_000540.3(RYR1):c.3495C>T (p.Gly1165=)

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.3495C>T (p.Gly1165=)

HGVS:

NC_000019.10:g.38469079C>T
NG_008866.1:g.40380C>T
NM_000540.3:c.3495C>TMANE SELECT
NM_001042723.2:c.3495C>T
NP_000531.2:p.Gly1165=
NP_000531.2:p.Gly1165=
NP_001036188.1:p.Gly1165=
LRG_766t1:c.3495C>T
LRG_766:g.40380C>T
LRG_766p1:p.Gly1165=
NC_000019.9:g.38959719C>T
NM_000540.2:c.3495C>T

Links:

dbSNP: rs772616442

NCBI 1000 Genomes Browser:

rs772616442

Molecular consequence:

NM_000540.3:c.3495C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001042723.2:c.3495C>T - synonymous variant - [Sequence Ontology: SO:0001819]

Observations:

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004358057	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 21, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30155738, 25741868
SCV004820812	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Sep 27, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30155738, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004358057

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 21, 2024)

germline

clinical testing

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

SCV004820812

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Sep 27, 2024)

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	15	not provided	not provided	143475	not provided	clinical testing

Citations

PubMed

Correlation of phenotype with genotype and protein structure in RYR1-related disorders.

Todd JJ, Sagar V, Lawal TA, Allen C, Razaqyar MS, Shelton MS, Chrismer IC, Zhang X, Cosgrove MM, Kuo A, Vasavada R, Jain MS, Waite M, Rajapakse D, Witherspoon JW, Wistow G, Meilleur KG.

J Neurol. 2018 Nov;265(11):2506-2524. doi: 10.1007/s00415-018-9033-2. Epub 2018 Aug 28.

PubMed [citation]

PMID:: 30155738
PMCID:: PMC6182665

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 Color Diagnostics, LLC DBA Color Health, SCV004358057.2

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

Description

This variant is located in the RYR1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with unspecified RYR1-related disorder (PMID: 30155738) and has not been reported in individuals with malignant hyperthermia susceptibility in the literature. This variant has been identified in 16/282864 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.

#	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

From All of Us Research Program, National Institutes of Health, SCV004820812.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	15	not provided	not provided	clinical testing	PubMed (2)

Description

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	143475	not provided	not provided		15	not provided	not provided	not provided

Last Updated: May 16, 2025

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