NM_000257.4(MYH7):c.2593A>G (p.Lys865Glu) AND Hypertrophic cardiomyopathy

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Mar 22, 2021
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000802005.9

Allele description [Variation Report for NM_000257.4(MYH7):c.2593A>G (p.Lys865Glu)]

NM_000257.4(MYH7):c.2593A>G (p.Lys865Glu)

Genes:

LOC126861898:BRD4-independent group 4 enhancer GRCh37_chr14:23893609-23894808 [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.2593A>G (p.Lys865Glu)

Other names:

p.K865E:AAG>GAG; NM_000257.4(MYH7):c.2593A>G; p.Lys865Glu

HGVS:

NC_000014.9:g.23424855T>C
NG_007884.1:g.15807A>G
NM_000257.4:c.2593A>GMANE SELECT
NP_000248.2:p.Lys865Glu
LRG_384t1:c.2593A>G
LRG_384:g.15807A>G
NC_000014.8:g.23894064T>C
NM_000257.2:c.2593A>G
NM_000257.3:c.2593A>G

Protein change:

K865E

Links:

dbSNP: rs730880749

NCBI 1000 Genomes Browser:

rs730880749

Molecular consequence:

NM_000257.4:c.2593A>G - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000941811	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 1, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27247418, 27532257, 28492532
SCV001842658	ClinGen Cardiomyopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen CMP ACMG Specifications v1)	Likely pathogenic (Mar 22, 2021)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000941811

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 1, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001842658

ClinGen Cardiomyopathy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen CMP ACMG Specifications v1)

Likely pathogenic
(Mar 22, 2021)

germline

curation

PubMed (1)
[See all records that cite this PMID]

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, curation

Citations

PubMed

Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.

Walsh R, Thomson KL, Ware JS, Funke BH, Woodley J, McGuire KJ, Mazzarotto F, Blair E, Seller A, Taylor JC, Minikel EV, Exome Aggregation Consortium, MacArthur DG, Farrall M, Cook SA, Watkins H.

Genet Med. 2017 Feb;19(2):192-203. doi: 10.1038/gim.2016.90. Epub 2016 Aug 17.

PubMed [citation]

PMID:: 27532257
PMCID:: PMC5116235

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000941811.6

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

Description

This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27247418; Invitae). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function. ClinVar contains an entry for this variant (Variation ID: 181195). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 865 of the MYH7 protein (p.Lys865Glu).

#	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 ClinGen Cardiomyopathy Variant Curation Expert Panel, SCV001842658.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

Description

The c.2593A>G (p.Lys865Glu) variant in MYH7 has been identified in 4 individuals with HCM (PS4_Supporting; Homburger 2016 PMID:27247418; GeneDx pers. comm., Invitae pers. comm.). This variant segregated with HCM in 5 affected relatives from 2 families (PP1_Moderate; GeneDx, pers. comm., Invitae pers. comm.). This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting; PP1_Moderate; PM2; PM1

#	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: Jan 13, 2025

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