NM_000540.3(RYR1):c.9800C>T (p.Pro3267Leu) AND Malignant hyperthermia, susceptibility to, 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 1, 2023
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:: RCV000209981.4

Allele description [Variation Report for NM_000540.3(RYR1):c.9800C>T (p.Pro3267Leu)]

NM_000540.3(RYR1):c.9800C>T (p.Pro3267Leu)

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.9800C>T (p.Pro3267Leu)

HGVS:

NC_000019.10:g.38517473C>T
NG_008866.1:g.88774C>T
NM_000540.3:c.9800C>TMANE SELECT
NM_001042723.2:c.9800C>T
NP_000531.2:p.Pro3267Leu
NP_000531.2:p.Pro3267Leu
NP_001036188.1:p.Pro3267Leu
LRG_766t1:c.9800C>T
LRG_766:g.88774C>T
LRG_766p1:p.Pro3267Leu
NC_000019.9:g.39008113C>T
NM_000540.2:c.9800C>T

Protein change:

P3267L

Links:

dbSNP: rs200375946

NCBI 1000 Genomes Browser:

rs200375946

Molecular consequence:

NM_000540.3:c.9800C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.9800C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000265732	Biesecker Lab/Clinical Genomics Section, National Institutes of Health - ClinSeq	criteria provided, single submitter (Gonsalves et al. 2013)	Uncertain significance (Jul 1, 2013)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV004819645	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 1, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000265732

Biesecker Lab/Clinical Genomics Section, National Institutes of Health - ClinSeq

criteria provided, single submitter

(Gonsalves et al. 2013)

Uncertain significance
(Jul 1, 2013)

unknown

research

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

SCV004819645

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 1, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	13	not provided	not provided	108544	not provided	clinical testing
not provided	unknown	unknown	3	not provided	not provided	not provided	not provided	research

Citations

PubMed

Using exome data to identify malignant hyperthermia susceptibility mutations.

Gonsalves SG, Ng D, Johnston JJ, Teer JK, Stenson PD, Cooper DN, Mullikin JC, Biesecker LG; NISC Comparative Sequencing Program..

Anesthesiology. 2013 Nov;119(5):1043-53. doi: 10.1097/ALN.0b013e3182a8a8e7.

PubMed [citation]

PMID:: 24195946
PMCID:: PMC4077354

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 Biesecker Lab/Clinical Genomics Section, National Institutes of Health - ClinSeq, SCV000265732.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		3	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004819645.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	13	not provided	not provided	clinical testing	PubMed (1)

Description

This missense variant replaces proline with leucine at codon 3267 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 14/281804 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	108544	not provided	not provided		13	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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