NM_000257.4(MYH7):c.4402G>A (p.Glu1468Lys) AND Cardiovascular phenotype

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 4, 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:: RCV000241907.3

Allele description [Variation Report for NM_000257.4(MYH7):c.4402G>A (p.Glu1468Lys)]

NM_000257.4(MYH7):c.4402G>A (p.Glu1468Lys)

Genes:

MYH7:myosin heavy chain 7 [Gene - OMIM - HGNC]
MHRT:myosin heavy chain associated RNA transcript [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q11.2

Genomic location:

Preferred name:

NM_000257.4(MYH7):c.4402G>A (p.Glu1468Lys)

HGVS:

NC_000014.9:g.23417270C>T
NG_007884.1:g.23392G>A
NM_000257.4:c.4402G>AMANE SELECT
NP_000248.2:p.Glu1468Lys
LRG_384t1:c.4402G>A
LRG_384:g.23392G>A
NC_000014.8:g.23886479C>T
NM_000257.2:c.4402G>A
NM_000257.3:c.4402G>A
NR_126491.1:n.710C>T

Protein change:

E1468K

Links:

dbSNP: rs876657884

NCBI 1000 Genomes Browser:

rs876657884

Molecular consequence:

NM_000257.4:c.4402G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_126491.1:n.710C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV000318193	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Mar 4, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 26656175, 27247418, 27737317, 30297972, 31199839, 32481709, 33495597, 33764162 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000318193

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Mar 4, 2024)

germline

clinical testing

PubMed (8)
[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

Molecular analysis of sarcomeric and non-sarcomeric genes in patients with hypertrophic cardiomyopathy.

Bottillo I, D'Angelantonio D, Caputo V, Paiardini A, Lipari M, De Bernardo C, Giannarelli D, Pizzuti A, Majore S, Castori M, Zachara E, Re F, Grammatico P.

Gene. 2016 Feb 15;577(2):227-35. doi: 10.1016/j.gene.2015.11.048. Epub 2015 Dec 2.

PubMed [citation]

PMID:: 26656175

Multidimensional structure-function relationships in human β-cardiac myosin from population-scale genetic variation.

Homburger JR, Green EM, Caleshu C, Sunitha MS, Taylor RE, Ruppel KM, Metpally RP, Colan SD, Michels M, Day SM, Olivotto I, Bustamante CD, Dewey FE, Ho CY, Spudich JA, Ashley EA.

Proc Natl Acad Sci U S A. 2016 Jun 14;113(24):6701-6. doi: 10.1073/pnas.1606950113. Epub 2016 May 31.

PubMed [citation]

PMID:: 27247418
PMCID:: PMC4914177

See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV000318193.7

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

Description

The p.E1468K variant (also known as c.4402G>A), located in coding exon 30 of the MYH7 gene, results from a G to A substitution at nucleotide position 4402. The glutamic acid at codon 1468 is replaced by lysine, an amino acid with similar properties. This alteration has been identified in multiple individuals with hypertrophic cardiomyopathy and has been shown to segregate with disease in several families (Bottillo I et al. Gene, 2016 Feb;577:227-35; Mattos BP et al. Arq. Bras. Cardiol., 2016 Sep;107:257-265; Ho CY et al. Circulation, 2018 Oct;138:1387-1398; external communication; Ambry internal data). However, a number of relatives positive for this alteration were reportedly unaffected, suggesting incomplete penetrance. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be 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: Oct 8, 2024

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