NM_000540.3(RYR1):c.14693T>C (p.Ile4898Thr) AND RYR1-related disorder

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 2, 2025
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:: RCV000535754.22

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:

UniProtKB: P21817#VAR_045771; OMIM: 180901.0012; dbSNP: 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)

Name:: RYR1-related disorder
Synonyms:: RYR1-related condition; RYR1-related disorders
Identifiers:: MedGen: CN239331

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000659857	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 2, 2025)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 11709545, 11741831, 20888934, 24561095, 25084811, 10097181, 12642598, 15175001, 21825032, 22203976, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000659857

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 2, 2025)

germline

clinical testing

PubMed (11)
[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

Familial and sporadic forms of central core disease are associated with mutations in the C-terminal domain of the skeletal muscle ryanodine receptor.

Monnier N, Romero NB, Lerale J, Landrieu P, Nivoche Y, Fardeau M, Lunardi J.

Hum Mol Genet. 2001 Oct 15;10(22):2581-92.

PubMed [citation]

PMID:: 11709545

Identification of four novel mutations in the C-terminal membrane spanning domain of the ryanodine receptor 1: association with central core disease and alteration of calcium homeostasis.

Tilgen N, Zorzato F, Halliger-Keller B, Muntoni F, Sewry C, Palmucci LM, Schneider C, Hauser E, Lehmann-Horn F, Müller CR, Treves S.

Hum Mol Genet. 2001 Dec 1;10(25):2879-87.

PubMed [citation]

PMID:: 11741831

See all PubMed Citations (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000659857.12

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 4898 of the RYR1 protein (p.Ile4898Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant central core disease (PMID: 10097181, 11709545, 11741831, 20888934, 24561095, 25084811). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as I4897T. ClinVar contains an entry for this variant (Variation ID: 12975). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 10097181, 12642598, 15175001, 21825032, 22203976). For these reasons, this variant has been classified as 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: Apr 4, 2026

ClinVar

Relating variation to medicine