NM_000540.3(RYR1):c.14126C>T (p.Thr4709Met) AND RYR1-related disorder

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 16, 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:: RCV000555087.12

Allele description [Variation Report for NM_000540.3(RYR1):c.14126C>T (p.Thr4709Met)]

NM_000540.3(RYR1):c.14126C>T (p.Thr4709Met)

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.14126C>T (p.Thr4709Met)

Other names:

NM_000540.3(RYR1):c.14126C>T

HGVS:

NC_000019.10:g.38573304C>T
NG_008866.1:g.144605C>T
NM_000540.3:c.14126C>TMANE SELECT
NM_001042723.2:c.14111C>T
NP_000531.2:p.Thr4709Met
NP_000531.2:p.Thr4709Met
NP_001036188.1:p.Thr4704Met
LRG_766t1:c.14126C>T
LRG_766:g.144605C>T
LRG_766p1:p.Thr4709Met
NC_000019.9:g.39063944C>T
NM_000540.2:c.14126C>T
NP_000531.2:p.T4709M

Protein change:

T4704M

Links:

dbSNP: rs118192140

NCBI 1000 Genomes Browser:

rs118192140

Molecular consequence:

NM_000540.3:c.14126C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.14111C>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
SCV000659841	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 16, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17483490, 23919265, 31055738, 1743490, 28492532
SCV000915831	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Likely pathogenic (Nov 12, 2018)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17483490, 29172004, 21062345, 23919265, 30155738 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000659841

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 16, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV000915831

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Likely pathogenic
(Nov 12, 2018)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

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

Diffusion Tensor Imaging: Tool for Tracking Injured Spinal Cord Fibres in Rat.

Murgoci AN, Baciak L, Cubinkova V, Smolek T, Tvrdik T, Juranek I, Kafka J, Cizkova D.

Neurochem Res. 2020 Jan;45(1):180-187. doi: 10.1007/s11064-019-02801-9. Epub 2019 May 4.

PubMed [citation]

PMID:: 31055738

Variance of neutral genetic variances within and between populations for a quantitative character.

Zeng ZB, Cockerham CC.

Genetics. 1991 Oct;129(2):535-53.

PubMed [citation]

PMID:: 1743490
PMCID:: PMC1204642

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000659841.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 4709 of the RYR1 protein (p.Thr4709Met). This variant is present in population databases (rs118192140, gnomAD 0.09%). This missense change has been observed in individuals with autosomal recessive congenital myopathy (PMID: 17483490, 23919265, 31055738; Invitae). ClinVar contains an entry for this variant (Variation ID: 65996). 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%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 1743490). 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

From Illumina Laboratory Services, Illumina, SCV000915831.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The RYR1 c.14126C>T (p.Thr4709Met) variant has been reported in at least five studies and is found in a total of five patients with RYR1-related disorders including central code disease, multiminicore disease, and neuromuscular disease including four in a compound heterozygous state and one in a heterozygous state (Zhou et al. 2007; Bevilacqua et al. 2011; Amburgey et al. 2013; Vill et al. 2017; Todd et al. 2018). The p.Thr4709Met variant was absent from 300 controls and is reported at a frequency of 0.000888 in the Ashkenazi Jewish population of the Genome Aggregation Database. Zhou et al. (2007) demonstrated greatly reduced levels of RYR1 protein in skeletal muscles of patients in whom the p.Thr4709Met heterozygous variant was expressed in the background of a second non-transcribed allele. Based on the evidence, the p.Thr4709Met variant is classified as likely pathogenic RYR1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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: Nov 10, 2024

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