NM_000540.3(RYR1):c.14051T>C (p.Phe4684Ser) AND RYR1-related disorder

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 28, 2023
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:: RCV003591681.2

Allele description [Variation Report for NM_000540.3(RYR1):c.14051T>C (p.Phe4684Ser)]

NM_000540.3(RYR1):c.14051T>C (p.Phe4684Ser)

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.14051T>C (p.Phe4684Ser)

HGVS:

NC_000019.10:g.38573229T>C
NG_008866.1:g.144530T>C
NM_000540.3:c.14051T>CMANE SELECT
NM_001042723.2:c.14036T>C
NP_000531.2:p.Phe4684Ser
NP_000531.2:p.Phe4684Ser
NP_001036188.1:p.Phe4679Ser
LRG_766t1:c.14051T>C
LRG_766:g.144530T>C
LRG_766p1:p.Phe4684Ser
NC_000019.9:g.39063869T>C
NC_000019.9:g.39063869T>C
NM_000540.2(RYR1):c.14051T>C
NM_000540.2:c.14051T>C
P21817:p.Phe4684Ser
p.(Phe4684Ser)

Protein change:

F4679S

Links:

UniProtKB: P21817#VAR_045747; dbSNP: rs193922864

NCBI 1000 Genomes Browser:

rs193922864

Molecular consequence:

NM_000540.3:c.14051T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.14036T>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
SCV004282746	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 28, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16163667, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004282746

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 28, 2023)

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

Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility.

Monnier N, Kozak-Ribbens G, Krivosic-Horber R, Nivoche Y, Qi D, Kraev N, Loke J, Sharma P, Tegazzin V, Figarella-Branger D, Roméro N, Mezin P, Bendahan D, Payen JF, Depret T, Maclennan DH, Lunardi J.

Hum Mutat. 2005 Nov;26(5):413-25.

PubMed [citation]

PMID:: 16163667

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, SCV004282746.1

#	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 phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 4684 of the RYR1 protein (p.Phe4684Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with malignant hyperthermia susceptibility (PMID: 16163667). ClinVar contains an entry for this variant (Variation ID: 133057). 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 with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	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: Oct 26, 2024

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