NM_000257.4(MYH7):c.2722C>G (p.Leu908Val) AND Primary familial hypertrophic cardiomyopathy

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 12, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000035820.15

Allele description [Variation Report for NM_000257.4(MYH7):c.2722C>G (p.Leu908Val)]

NM_000257.4(MYH7):c.2722C>G (p.Leu908Val)

Gene:

MYH7:myosin heavy chain 7 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q11.2

Genomic location:

Preferred name:

NM_000257.4(MYH7):c.2722C>G (p.Leu908Val)

Other names:

p.L908V:CTG>GTG; NM_000257.3(MYH7):c.2722C>G

HGVS:

NC_000014.9:g.23424107G>C
NG_007884.1:g.16555C>G
NM_000257.4:c.2722C>GMANE SELECT
NP_000248.2:p.Leu908Val
NP_000248.2:p.Leu908Val
LRG_384t1:c.2722C>G
LRG_384:g.16555C>G
LRG_384p1:p.Leu908Val
NC_000014.8:g.23893316G>C
NM_000257.2:c.2722C>G
NM_000257.3:c.2722C>G
P12883:p.Leu908Val
c.2722C>G

Protein change:

L908V; LEU908VAL

Links:

UniProtKB: P12883#VAR_004593; OMIM: 160760.0010; dbSNP: rs121913631

NCBI 1000 Genomes Browser:

rs121913631

Molecular consequence:

NM_000257.4:c.2722C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Primary familial hypertrophic cardiomyopathy (HCM)
Synonyms:: Hereditary ventricular hypertrophy; Idiopathic hypertrophic subaortic stenosis
Identifiers:: MONDO: MONDO:0024573; MeSH: D024741; MedGen: C0949658; OMIM: PS192600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000264086	Blueprint Genetics	criteria provided, single submitter (Variant Classification)	Pathogenic (Nov 4, 2015)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 1638703, 7731997, 8435239, 8483915, 12473556, 12975413, 15358028, 8514894, 11227787, 15528230 Citation Link,
SCV000917841	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 12, 2021)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 12473556, 9172070, 1638703, 8483915, 8281650, 11227787, 15528230, 8514894, 18403758, 27532257 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000264086

Blueprint Genetics

criteria provided, single submitter

(Variant Classification)

Pathogenic
(Nov 4, 2015)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

Citation Link,

SCV000917841

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jul 12, 2021)

germline

clinical testing

PubMed (10)
[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	2	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

Structural interpretation of the mutations in the beta-cardiac myosin that have been implicated in familial hypertrophic cardiomyopathy.

Rayment I, Holden HM, Sellers JR, Fananapazir L, Epstein ND.

Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3864-8.

PubMed [citation]

PMID:: 7731997
PMCID:: PMC42062

Identification of a mutation in the beta cardiac myosin heavy chain gene in a family with hypertrophic cardiomyopathy.

al-Mahdawi S, Chamberlain S, Cleland J, Nihoyannopoulos P, Gilligan D, French J, Choudhury L, Williamson R, Oakley C.

Br Heart J. 1993 Feb;69(2):136-41.

PubMed [citation]

PMID:: 8435239
PMCID:: PMC1024940

See all PubMed Citations (14)

Details of each submission

From Blueprint Genetics, SCV000264086.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (10)

#	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		2	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917841.2

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

Description

Variant summary: MYH7 c.2722C>G (p.Leu908Val) results in a conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251552 control chromosomes. c.2722C>G has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (example, Epstein_1992, VanDriest_2002, Morita_2008, Alpert_2005, Alpert_2005, Walsh_2017). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The rate of translocation of acting filaments as measured by in-vitro motility assays was 35% of wild-type levels (Cuda_1993). Subsequently, a gain of function effect was observed as an increase in actin filament velocity in the in-vitro motility assay (Palmiter_2000) and an increase in actin sliding velocity (Alpert_2005). Multiple clinical diagnostic laboratories and an expert panel (ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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

Last Updated: Nov 3, 2024

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