NM_000257.4(MYH7):c.715G>A (p.Asp239Asn) AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 15, 2024
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:: RCV000622036.5

Allele description [Variation Report for NM_000257.4(MYH7):c.715G>A (p.Asp239Asn)]

NM_000257.4(MYH7):c.715G>A (p.Asp239Asn)

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.715G>A (p.Asp239Asn)

Other names:

NM_000257.4(MYH7):c.715G>A

HGVS:

NC_000014.9:g.23431602C>T
NG_007884.1:g.9060G>A
NM_000257.4:c.715G>AMANE SELECT
NP_000248.2:p.Asp239Asn
LRG_384t1:c.715G>A
LRG_384:g.9060G>A
NC_000014.8:g.23900811C>T
NM_000257.2:c.715G>A
NM_000257.3:c.715G>A
c.715G>A

Protein change:

D239N

Links:

dbSNP: rs397516264

NCBI 1000 Genomes Browser:

rs397516264

Molecular consequence:

NM_000257.4:c.715G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000740109	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Apr 15, 2024)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 17438619, 20031618, 21896538, 26743238, 26914223, 27247418, 27532257, 27974200, 28138913, 28408708, 28615295, 31006259 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000740109

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Apr 15, 2024)

germline

clinical testing

PubMed (12)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Gene symbol: MYH7.

Iascone MR, Marchetti D, Ferrazzi P.

Hum Genet. 2007 Feb;120(6):916. No abstract available.

PubMed [citation]

PMID:: 17438619

Prevalence of sarcomere protein gene mutations in preadolescent children with hypertrophic cardiomyopathy.

Kaski JP, Syrris P, Esteban MT, Jenkins S, Pantazis A, Deanfield JE, McKenna WJ, Elliott PM.

Circ Cardiovasc Genet. 2009 Oct;2(5):436-41. doi: 10.1161/CIRCGENETICS.108.821314. Epub 2009 Jul 16.

PubMed [citation]

PMID:: 20031618

See all PubMed Citations (12)

Details of each submission

From Ambry Genetics, SCV000740109.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

The p.D239N pathogenic mutation (also known as c.715G>A), located in coding exon 6 of the MYH7 gene, results from a G to A substitution at nucleotide position 715. The aspartic acid at codon 239 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in several individuals with hypertrophic cardiomyopathy (HCM), often characterized by an early age of onset (Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6; Kaski JP et al. Circ Cardiovasc Genet, 2009 Oct;2:436-41; Murphy SL et al. J Cardiovasc Transl Res, 2016 Apr;9:153-61; Garcia-Pavia P et al. Eur. J. Heart Fail., 2011 Nov;13:1193-201; Iascone MR et al. Hum. Genet., 2007 Feb;120:916; Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10; Adler A et al. Circ Arrhythm Electrophysiol, 2016 Jan;9:e003440; Alejandra Restrepo-Cordoba M et al. J Cardiovasc Transl Res, 2017 Feb;10:35-46; Ingles J et al. Circ Cardiovasc Genet, 2017 Apr;10; Norrish G et al. Circulation, 2019 07;140:184-192; Walsh R et al. Genet. Med., 2017 02;19:192-203). This alteration has been described to segregate with HCM in multiple families (Garcia-Pavia P et al. Eur. J. Heart Fail., 2011 Nov;13:1193-201; Iascone MR et al. Hum. Genet., 2007 Feb;120:916). Functional in vitro analyses have suggested this variant increases catalytic rate, velocity, and generation of force and therefore may adversely affect ventricular contraction (Adhikari AS et al. Cell Rep. 2016;17:2857-2864). This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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: Sep 29, 2024

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