NM_000258.3(MYL3):c.466G>A (p.Val156Met) AND Cardiomyopathy

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Mar 21, 2023
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:: RCV000769165.8

Allele description [Variation Report for NM_000258.3(MYL3):c.466G>A (p.Val156Met)]

NM_000258.3(MYL3):c.466G>A (p.Val156Met)

Gene:

MYL3:myosin light chain 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p21.31

Genomic location:

Preferred name:

NM_000258.3(MYL3):c.466G>A (p.Val156Met)

Other names:

p.V156M:GTG>ATG

HGVS:

NC_000003.12:g.46859490C>T
NG_007555.2:g.27680G>A
NM_000258.3:c.466G>AMANE SELECT
NP_000249.1:p.Val156Met
NP_000249.1:p.Val156Met
LRG_395t1:c.466G>A
LRG_395:g.27680G>A
LRG_395p1:p.Val156Met
NC_000003.11:g.46900980C>T
NM_000258.2:c.466G>A
c.466G>A
p.(Val156Met)

Protein change:

V156M

Links:

Leiden Muscular Dystrophy (MYL3): MYL3_00006; dbSNP: rs199474707

NCBI 1000 Genomes Browser:

rs199474707

Molecular consequence:

NM_000258.3:c.466G>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

functional variant [Sequence Ontology: SO:0001536]

Condition(s)

Name:: Cardiomyopathy (CMYO)
Synonyms:: Cardiomyopathies
Identifiers:: MONDO: MONDO:0004994; MedGen: C0878544; Human Phenotype Ontology: HP:0001638

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000900540	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario - Canadian Open Genetics Repository	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 21, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001344277	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 17, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16754800, 23549607, 24111713, 27532257, 33495597, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000900540

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario - Canadian Open Genetics Repository

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 21, 2023)

germline

clinical testing

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

SCV001344277

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 17, 2022)

germline

clinical testing

PubMed (6)
[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

Single-gene mutations and increased left ventricular wall thickness in the community: the Framingham Heart Study.

Morita H, Larson MG, Barr SC, Vasan RS, O'Donnell CJ, Hirschhorn JN, Levy D, Corey D, Seidman CE, Seidman JG, Benjamin EJ.

Circulation. 2006 Jun 13;113(23):2697-705. Epub 2006 Jun 5.

PubMed [citation]

PMID:: 16754800

T1 measurements identify extracellular volume expansion in hypertrophic cardiomyopathy sarcomere mutation carriers with and without left ventricular hypertrophy.

Ho CY, Abbasi SA, Neilan TG, Shah RV, Chen Y, Heydari B, Cirino AL, Lakdawala NK, Orav EJ, González A, López B, Díez J, Jerosch-Herold M, Kwong RY.

Circ Cardiovasc Imaging. 2013 May 1;6(3):415-22. doi: 10.1161/CIRCIMAGING.112.000333. Epub 2013 Apr 2.

PubMed [citation]

PMID:: 23549607
PMCID:: PMC3769196

See all PubMed Citations (6)

Details of each submission

From CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario - Canadian Open Genetics Repository, SCV000900540.3

#	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

From Color Diagnostics, LLC DBA Color Health, SCV001344277.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This missense variant replaces valine with methionine at codon 156 of the MYL3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 23549607, 24111713, 27532257, 33495597) and in an individual showing early signs of left ventricular wall thickening (PMID 16754800). This variant has been identified in 6/282752 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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 26, 2024

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