NM_000432.4(MYL2):c.119G>A (p.Arg40Lys) AND Cardiovascular phenotype

Germline classification:: Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:: Apr 23, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV002345474.3

Allele description [Variation Report for NM_000432.4(MYL2):c.119G>A (p.Arg40Lys)]

NM_000432.4(MYL2):c.119G>A (p.Arg40Lys)

Gene:

MYL2:myosin light chain 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q24.11

Genomic location:

Preferred name:

NM_000432.4(MYL2):c.119G>A (p.Arg40Lys)

Other names:

p.R40K:AGG>AAG

HGVS:

NC_000012.12:g.110915765C>T
NG_007554.1:g.9813G>A
NM_000432.4:c.119G>AMANE SELECT
NP_000423.2:p.Arg40Lys
NP_000423.2:p.Arg40Lys
LRG_393t1:c.119G>A
LRG_393:g.9813G>A
LRG_393p1:p.Arg40Lys
NC_000012.11:g.111353569C>T
NM_000432.3:c.119G>A

Protein change:

R40K

Links:

dbSNP: rs727503299

NCBI 1000 Genomes Browser:

rs727503299

Molecular consequence:

NM_000432.4:c.119G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000740465	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 23, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002640820	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Aug 18, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24111713, 25132132, 27532257 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000740465

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Apr 23, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002640820

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Aug 18, 2021)

germline

clinical testing

PubMed (3)
[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	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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Genetics of hypertrophic cardiomyopathy in Norway.

Berge KE, Leren TP.

Clin Genet. 2014 Oct;86(4):355-60. doi: 10.1111/cge.12286. Epub 2013 Oct 23.

PubMed [citation]

PMID:: 24111713

See all PubMed Citations (4)

Details of each submission

From Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute, SCV000740465.2

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

Description

PM2;PP1_mod;PS4_supp;PP2

#	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 Ambry Genetics, SCV002640820.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The p.R40K variant (also known as c.119G>A), located in coding exon 3 of the MYL2 gene, results from a G to A substitution at nucleotide position 119. The arginine at codon 40 is replaced by lysine, an amino acid with highly similar properties. This variant has been reported in individuals with hypertrophic cardiomyopathy (HCM) and in HCM genetic testing cohorts; however, clinical details have been limited (Wang J et al. Eur J Heart Fail, 2014 Sep;16:950-7; Berge KE et al. Clin Genet, 2014 Oct;86:355-60; Walsh R et al. Genet Med, 2017 02;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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: May 16, 2025

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