NM_000540.3(RYR1):c.14917C>T (p.Pro4973Ser) AND RYR1-related disorder

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 31, 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:: RCV002031895.5

Allele description [Variation Report for NM_000540.3(RYR1):c.14917C>T (p.Pro4973Ser)]

NM_000540.3(RYR1):c.14917C>T (p.Pro4973Ser)

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.14917C>T (p.Pro4973Ser)

HGVS:

NC_000019.10:g.38586139C>T
NG_008866.1:g.157440C>T
NM_000540.3:c.14917C>TMANE SELECT
NM_001042723.2:c.14902C>T
NP_000531.2:p.Pro4973Ser
NP_001036188.1:p.Pro4968Ser
LRG_766:g.157440C>T
NC_000019.9:g.39076779C>T

Protein change:

P4968S

Links:

dbSNP: rs747622915

NCBI 1000 Genomes Browser:

rs747622915

Molecular consequence:

NM_000540.3:c.14917C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.14902C>T - 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
SCV002311489	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 31, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12411788, 25957634, 28687594, 29169929, 30236257, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002311489

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 31, 2021)

germline

clinical testing

PubMed (6)
[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

Presence of two different genetic traits in malignant hyperthermia families: implication for genetic analysis, diagnosis, and incidence of malignant hyperthermia susceptibility.

Monnier N, Krivosic-Horber R, Payen JF, Kozak-Ribbens G, Nivoche Y, Adnet P, Reyford H, Lunardi J.

Anesthesiology. 2002 Nov;97(5):1067-74.

PubMed [citation]

PMID:: 12411788

Centronuclear myopathies: genotype-phenotype correlation and frequency of defined genetic forms in an Italian cohort.

Fattori F, Maggi L, Bruno C, Cassandrini D, Codemo V, Catteruccia M, Tasca G, Berardinelli A, Magri F, Pane M, Rubegni A, Santoro L, Ruggiero L, Fiorini P, Pini A, Mongini T, Messina S, Brisca G, Colombo I, Astrea G, Fiorillo C, Bragato C, et al.

J Neurol. 2015 Jul;262(7):1728-40. doi: 10.1007/s00415-015-7757-9. Epub 2015 May 10.

PubMed [citation]

PMID:: 25957634

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002311489.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces proline with serine at codon 4973 of the RYR1 protein (p.Pro4973Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs747622915, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. 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: "Not Available"; Align-GVGD: "Class C0"). This variant disrupts the p.Pro4973 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12411788, 25957634, 28687594, 29169929, 30236257). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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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