NM_000540.3(RYR1):c.14693T>C (p.Ile4898Thr) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Apr 30, 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:: RCV000119552.20

Allele description [Variation Report for NM_000540.3(RYR1):c.14693T>C (p.Ile4898Thr)]

NM_000540.3(RYR1):c.14693T>C (p.Ile4898Thr)

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.14693T>C (p.Ile4898Thr)

Other names:

NM_000540.3(RYR1):c.14693T>C

HGVS:

NC_000019.10:g.38584989T>C
NG_008866.1:g.156290T>C
NM_000540.3:c.14693T>CMANE SELECT
NM_001042723.2:c.14678T>C
NP_000531.2:p.Ile4898Thr
NP_000531.2:p.Ile4898Thr
NP_001036188.1:p.Ile4893Thr
LRG_766t1:c.14693T>C
LRG_766:g.156290T>C
LRG_766p1:p.Ile4898Thr
NC_000019.9:g.39075629T>C
NM_000540.2:c.14693T>C
NM_000540.3:c.14693T>C
P21817:p.Ile4898Thr
p.(Ile4898Thr)

Protein change:

I4893T; ILE4898THR

Links:

PharmGKB: 1183705788PA164749136; PharmGKB: 1183705788PA449461; PharmGKB: 1183705788PA449845; PharmGKB: 1183705788PA450106; PharmGKB: 1183705788PA450434; PharmGKB: 1183705788PA451341; PharmGKB: 1183705788PA451522; UniProtKB: P21817#VAR_045771; OMIM: 180901.0012; dbSNP: rs118192170

NCBI 1000 Genomes Browser:

rs118192170

Molecular consequence:

NM_000540.3:c.14693T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.14678T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000154459	Leiden Muscular Dystrophy (RYR1)	no classification provided	not provided	unknown	not provided	PubMed (2) [See all records that cite these PMIDs] 16621918, 17081152
SCV000852452	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 15, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001781945	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 30, 2024)	germline	clinical testing	Citation Link,
SCV002019927	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 26, 2021)	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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	not provided	not provided	not provided	not provided	1	not provided	literature only

Citations

PubMed

Central core disease is due to RYR1 mutations in more than 90% of patients.

Wu S, Ibarra MC, Malicdan MC, Murayama K, Ichihara Y, Kikuchi H, Nonaka I, Noguchi S, Hayashi YK, Nishino I.

Brain. 2006 Jun;129(Pt 6):1470-80. Epub 2006 Apr 18.

PubMed [citation]

PMID:: 16621918

Malignant hyperthermia and central core disease causative mutations in Swedish patients.

Broman M, Islander G, Müller CR, Ranklev-Twetman E.

Acta Anaesthesiol Scand. 2007 Jan;51(1):50-3. Epub 2006 Nov 1.

PubMed [citation]

PMID:: 17081152

See all PubMed Citations (3)

Details of each submission

From Leiden Muscular Dystrophy (RYR1), SCV000154459.1

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

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

From PreventionGenetics, part of Exact Sciences, SCV000852452.1

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

#	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 GeneDx, SCV001781945.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Published functional studies demonstrate a damaging effect as this variant results in altered calcium conductance, with little to no calcium release, reduced luminal calcium storage, and increased cytoplasmic calcium levels (PMID: 10097181); Mouse model study demonstrates I4898T results in absent voltage-induced calcium release (PMID: 22203976); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15175001, 15299003, 21825032, 29629541, 16084090, 32403337, 20961389, 20461000, 12642598, 11274444, 12161072, 25084811, 27363342, 11741831, 11709545, 24561095, 35428369, 32721234, 18003898, 33458582, 32140910, 34008892, 25214167, 35693006, 20681998, 33767344, 19959667, 32528171, 33333461, 20888934, 22203976, 10097181)

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

From Revvity Omics, Revvity, SCV002019927.3

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

#	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 8, 2024

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