NM_000257.4(MYH7):c.4377G>T (p.Lys1459Asn) AND Cardiomyopathy

Germline classification:: Likely benign (4 submissions)
Last evaluated:: Dec 15, 2016
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:: RCV000758029.21

Allele description [Variation Report for NM_000257.4(MYH7):c.4377G>T (p.Lys1459Asn)]

NM_000257.4(MYH7):c.4377G>T (p.Lys1459Asn)

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.4377G>T (p.Lys1459Asn)

Other names:

NM_000257.3(MYH7):c.4377G>T

HGVS:

NC_000014.9:g.23417295C>A
NG_007884.1:g.23367G>T
NM_000257.4:c.4377G>TMANE SELECT
NP_000248.2:p.Lys1459Asn
LRG_384t1:c.4377G>T
LRG_384:g.23367G>T
NC_000014.8:g.23886504C>A
NM_000257.2:c.4377G>T
NM_000257.3:c.4377G>T
NR_126491.1:n.735C>A
P12883:p.Lys1459Asn
c.4377G>T

Protein change:

K1459N

Links:

UniProtKB: P12883#VAR_042828; dbSNP: rs201307101

NCBI 1000 Genomes Browser:

rs201307101

Molecular consequence:

NM_000257.4:c.4377G>T - missense variant - [Sequence Ontology: SO:0001583]
NR_126491.1:n.735C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Cardiomyopathy (CMYO)
Synonyms:: Cardiomyopathies
Identifiers:: MONDO: MONDO:0004994; MedGen: C0878544; Human Phenotype Ontology: HP:0001638

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000577982	ClinGen Cardiomyopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen CMP ACMG Specifications v1)	Likely benign (Dec 15, 2016)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000913884	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 24, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 17125710, 19150014, 21127202, 22765922, 24793961, 28356264, 30871747, 25741868
SCV001333659	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Dec 7, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004814377	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jan 11, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 17125710, 19150014, 21127202, 22765922, 24793961, 28356264, 30871747, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	66	not provided	not provided	108544	not provided	clinical testing, curation

Citations

PubMed

Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel.

Kelly MA, Caleshu C, Morales A, Buchan J, Wolf Z, Harrison SM, Cook S, Dillon MW, Garcia J, Haverfield E, Jongbloed JDH, Macaya D, Manrai A, Orland K, Richard G, Spoonamore K, Thomas M, Thomson K, Vincent LM, Walsh R, Watkins H, Whiffin N, et al.

Genet Med. 2018 Mar;20(3):351-359. doi: 10.1038/gim.2017.218. Epub 2018 Jan 4.

PubMed [citation]

PMID:: 29300372
PMCID:: PMC5876064

[Beta-myosin heavy-chain gene mutations in patients with hypertrophic cardiomyopathy].

Laredo R, Monserrat L, Hermida-Prieto M, Fernández X, Rodríguez I, Cazón L, Alvariño I, Dumont C, Piñón P, Peteiro J, Bouzas B, Castro-Beiras A.

Rev Esp Cardiol. 2006 Oct;59(10):1008-18. Spanish. Erratum in: Rev Esp Cardiol. 2007 May;60(5):557.

PubMed [citation]

PMID:: 17125710

See all PubMed Citations (9)

Details of each submission

From ClinGen Cardiomyopathy Variant Curation Expert Panel, SCV000577982.6

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

Description

The filtering allele frequency of the c.4377G>T (p.Lys1459Asn) variant in the MYH7 gene is 0.0375% (34/66566) of European chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; PMID:29300372). Additionally, while computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3), this pathogenic evidence code (PP3) was not considered to be in conflict with a likely benign conclusion given the accuracy of computation prediction tools. In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PP3; BS1

#	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 Color Diagnostics, LLC DBA Color Health, SCV000913884.5

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

Description

This missense variant replaces lysine with asparagine at codon 1459 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 17125710, 19150014, 22765922, 24793961, 28356264), in an individual affected with Ebstein anomaly (PMID: 21127202), and in an individual affected with dilated cardiomyopathy (PMID: 30871747). This variant has also been identified in 83/282640 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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 CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario, SCV001333659.3

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

#	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 All of Us Research Program, National Institutes of Health, SCV004814377.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	66	not provided	not provided	clinical testing	PubMed (8)

Description

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		66	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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