NM_000258.3(MYL3):c.466G>T (p.Val156Leu) AND Hypertrophic cardiomyopathy

This record was updated by the submitter. Please see the current version.

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Nov 17, 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:: RCV001309098.4

Allele description

NM_000258.3(MYL3):c.466G>T (p.Val156Leu)

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>T (p.Val156Leu)

Other names:

p.V156L:GTG>TTG

HGVS:

NC_000003.12:g.46859490C>A
NG_007555.2:g.27680G>T
NM_000258.3:c.466G>TMANE SELECT
NP_000249.1:p.Val156Leu
NP_000249.1:p.Val156Leu
LRG_395t1:c.466G>T
LRG_395:g.27680G>T
LRG_395p1:p.Val156Leu
NC_000003.11:g.46900980C>A
NM_000258.2:c.466G>T

Protein change:

V156L

Links:

dbSNP: rs199474707

NCBI 1000 Genomes Browser:

rs199474707

Molecular consequence:

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

Observations:

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001498581	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 17, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 25132132, 25611685, 31737537, 16754800, 23549607, 24111713, 27532257, 28492532
SCV004843319	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Oct 2, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 25132132, 27532257, 30630173, 31737537, 33495596, 35026164, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001498581

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 17, 2023)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV004843319

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Oct 2, 2023)

germline

clinical testing

PubMed (7)
[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	3	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity.

Alfares AA, Kelly MA, McDermott G, Funke BH, Lebo MS, Baxter SB, Shen J, McLaughlin HM, Clark EH, Babb LJ, Cox SW, DePalma SR, Ho CY, Seidman JG, Seidman CE, Rehm HL.

Genet Med. 2015 Nov;17(11):880-8. doi: 10.1038/gim.2014.205. Epub 2015 Jan 22. Erratum in: Genet Med. 2015 Apr;17(4):319.

PubMed [citation]

PMID:: 25611685

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

See all PubMed Citations (12)

Details of each submission

From Invitae, SCV001498581.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 156 of the MYL3 protein (p.Val156Leu). This variant is present in population databases (rs199474707, gnomAD 0.002%). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 25132132, 25611685, 27532257, 31737537; Invitae). ClinVar contains an entry for this variant (Variation ID: 177841). 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.Val156 amino acid residue in MYL3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16754800, 23549607, 24111713, 27532257; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 All of Us Research Program, National Institutes of Health, SCV004843319.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (7)

Description

This missense variant replaces valine with leucine at codon 156 in the EF-hand domain of the MYL3 protein. Computational prediction suggests that this variant may have a 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, and a different nucleotide change resulting in the same codon change, MYL3 c.466G>C p.Val156Leu, have been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 25132132, 27532257, 31737537, 33495596, 35026164; communication with an external laboratory; ClinVar SCV001498581.2). This variant has also been reported in an individual affected with dilated cardiomyopathy and ventricular tachycardia (PMID: 30630173). This variant has been identified in 3/251364 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		3	not provided	not provided	not provided

Last Updated: Apr 20, 2024

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