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

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 31, 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:: RCV000196294.11

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]

Observations:

Condition(s)

Name:: Hypertrophic cardiomyopathy
Synonyms:: HYPERTROPHIC MYOCARDIOPATHY
Identifiers:: MONDO: MONDO:0005045; MeSH: D002312; MedGen: C0007194; Human Phenotype Ontology: HP:0001639

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
SCV000254449	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16754800, 23549607, 24111713, 27532257, 25132132, 28492532
SCV004843320	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Aug 15, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 23549607, 24111713, 27532257, 33495597, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000254449

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 31, 2024)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV004843320

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Aug 15, 2023)

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	unknown	10	not provided	not provided	108544	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

Malignant effects of multiple rare variants in sarcomere genes on the prognosis of patients with hypertrophic cardiomyopathy.

Wang J, Wang Y, Zou Y, Sun K, Wang Z, Ding H, Yuan J, Wei W, Hou Q, Wang H, Liu X, Zhang H, Ji Y, Zhou X, Sharma RK, Wang D, Ahmad F, Hui R, Song L.

Eur J Heart Fail. 2014 Sep;16(9):950-7. doi: 10.1002/ejhf.144. Epub 2014 Jul 31.

PubMed [citation]

PMID:: 25132132

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000254449.8

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

Description

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 156 of the MYL3 protein (p.Val156Met). This variant is present in population databases (rs199474707, gnomAD 0.004%). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 16754800, 23549607, 24111713, 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 31778). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Met156 amino acid residue in MYL3. Other variant(s) that disrupt this residue have been observed in individuals with MYL3-related conditions (PMID: 25132132), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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 All of Us Research Program, National Institutes of Health, SCV004843320.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	10	not provided	not provided	clinical testing	PubMed (5)

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	108544	not provided	not provided		10	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine