NM_000432.4(MYL2):c.497A>T (p.Asp166Val) AND Hypertrophic cardiomyopathy 10

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 27, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001852571.3

Allele description [Variation Report for NM_000432.4(MYL2):c.497A>T (p.Asp166Val)]

NM_000432.4(MYL2):c.497A>T (p.Asp166Val)

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.497A>T (p.Asp166Val)

HGVS:

NC_000012.12:g.110911081T>A
NG_007554.1:g.14497A>T
NM_000432.4:c.497A>TMANE SELECT
NP_000423.2:p.Asp166Val
NP_000423.2:p.Asp166Val
LRG_393t1:c.497A>T
LRG_393:g.14497A>T
LRG_393p1:p.Asp166Val
NC_000012.11:g.111348885T>A
NM_000432.3:c.497A>T
P10916:p.Asp166Val
p.(Asp166Val)

Protein change:

D166V

Links:

Leiden Muscular Dystrophy (MYL2): MYL2_00010; UniProtKB: P10916#VAR_019844; dbSNP: rs199474815

NCBI 1000 Genomes Browser:

rs199474815

Molecular consequence:

NM_000432.4:c.497A>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

functional variant [Sequence Ontology: SO:0001536]

Condition(s)

Name:: Hypertrophic cardiomyopathy 10
Synonyms:: CARDIOMYOPATHY, HYPERTROPHIC, MID-LEFT VENTRICULAR CHAMBER TYPE, 2; Familial hypertrophic cardiomyopathy 10; MYL2-Related Familial Hypertrophic Cardiomyopathy
Identifiers:: MONDO: MONDO:0012112; MedGen: C1834460; OMIM: 608758

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002303693	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jun 27, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18987303, 23727233, 24374283, 12707239, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002303693

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jun 27, 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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Malignant familial hypertrophic cardiomyopathy D166V mutation in the ventricular myosin regulatory light chain causes profound effects in skinned and intact papillary muscle fibers from transgenic mice.

Kerrick WG, Kazmierczak K, Xu Y, Wang Y, Szczesna-Cordary D.

FASEB J. 2009 Mar;23(3):855-65. doi: 10.1096/fj.08-118182. Epub 2008 Nov 5.

PubMed [citation]

PMID:: 18987303
PMCID:: PMC2653985

Diversity and similarity of motor function and cross-bridge kinetics in papillary muscles of transgenic mice carrying myosin regulatory light chain mutations D166V and R58Q.

Wang L, Muthu P, Szczesna-Cordary D, Kawai M.

J Mol Cell Cardiol. 2013 Sep;62:153-63. doi: 10.1016/j.yjmcc.2013.05.012. Epub 2013 May 29.

PubMed [citation]

PMID:: 23727233
PMCID:: PMC3809071

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV002303693.3

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

Description

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. Experimental studies have shown that this missense change affects MYL2 function (PMID: 18987303, 23727233, 24374283). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 31769). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 12707239; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 166 of the MYL2 protein (p.Asp166Val).

#	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: Feb 28, 2024

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