NM_000540.3(RYR1):c.7268T>A (p.Met2423Lys) AND RYR1-related disorder

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 11, 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:: RCV001851835.9

Allele description [Variation Report for NM_000540.3(RYR1):c.7268T>A (p.Met2423Lys)]

NM_000540.3(RYR1):c.7268T>A (p.Met2423Lys)

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.7268T>A (p.Met2423Lys)

HGVS:

NC_000019.10:g.38499961T>A
NG_008866.1:g.71262T>A
NM_000540.3:c.7268T>AMANE SELECT
NM_001042723.2:c.7268T>A
NP_000531.2:p.Met2423Lys
NP_000531.2:p.Met2423Lys
NP_001036188.1:p.Met2423Lys
LRG_766t1:c.7268T>A
LRG_766:g.71262T>A
LRG_766p1:p.Met2423Lys
NC_000019.9:g.38990601T>A
NM_000540.2:c.7268T>A
P21817:p.Met2423Lys

Protein change:

M2423K; MET2423LYS

Links:

UniProtKB: P21817#VAR_032915; OMIM: 180901.0027; dbSNP: rs118192174

NCBI 1000 Genomes Browser:

rs118192174

Molecular consequence:

NM_000540.3:c.7268T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.7268T>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV002232164	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 11, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17033962, 18253926, 21911697, 30611313, 28492532
SCV002526405	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 10, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17483490, 17365175, 17033962, 16380615, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002232164

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 11, 2024)

germline

clinical testing

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

SCV002526405

DASA

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 10, 2022)

germline

clinical testing

PubMed (5)
[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	yes	1	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

Citations

PubMed

Null mutations causing depletion of the type 1 ryanodine receptor (RYR1) are commonly associated with recessive structural congenital myopathies with cores.

Monnier N, Marty I, Faure J, Castiglioni C, Desnuelle C, Sacconi S, Estournet B, Ferreiro A, Romero N, Laquerriere A, Lazaro L, Martin JJ, Morava E, Rossi A, Van der Kooi A, de Visser M, Verschuuren C, Lunardi J.

Hum Mutat. 2008 May;29(5):670-8. doi: 10.1002/humu.20696.

PubMed [citation]

PMID:: 18253926

Muscle magnetic resonance imaging in congenital myopathies due to ryanodine receptor type 1 gene mutations.

Klein A, Jungbluth H, Clement E, Lillis S, Abbs S, Munot P, Pane M, Wraige E, Schara U, Straub V, Mercuri E, Muntoni F.

Arch Neurol. 2011 Sep;68(9):1171-9. doi: 10.1001/archneurol.2011.188.

PubMed [citation]

PMID:: 21911697

See all PubMed Citations (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002232164.3

#	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 methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 2423 of the RYR1 protein (p.Met2423Lys). This variant is present in population databases (rs118192174, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive congenital myopathy (PMID: 17033962, 18253926, 21911697, 30611313). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12989). 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 80%. 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 DASA, SCV002526405.1

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

Description

The c.7268T>A;p.(Met2423Lys) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 12989; OMIM: 180901.0027; PMID: 17483490; 17365175; 17033962; 16380615) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (central region) - PM1. The variant is present at low allele frequencies population databases (rs118192174– gnomAD 0.0001987%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 17033962; PMID: 16380615) - PP1_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic

#	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		1	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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