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NM_000257.4(MYH7):c.4276G>A (p.Glu1426Lys) AND Primary dilated cardiomyopathy

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Sep 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:
RCV000758069.2

Allele description [Variation Report for NM_000257.4(MYH7):c.4276G>A (p.Glu1426Lys)]

NM_000257.4(MYH7):c.4276G>A (p.Glu1426Lys)

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.4276G>A (p.Glu1426Lys)
Other names:
NM_000257.3(MYH7):c.4276G>A; NM_000257.4(MYH7):c.4276G>A
HGVS:
  • NC_000014.9:g.23417580C>T
  • NG_007884.1:g.23082G>A
  • NM_000257.4:c.4276G>AMANE SELECT
  • NP_000248.2:p.Glu1426Lys
  • LRG_384t1:c.4276G>A
  • LRG_384:g.23082G>A
  • NC_000014.8:g.23886789C>T
  • NM_000257.2:c.4276G>A
  • NM_000257.3:c.4276G>A
  • NR_126491.1:n.861C>T
  • P12883:p.Glu1426Lys
  • c.4276G>A
Protein change:
E1426K
Links:
UniProtKB: P12883#VAR_042826; dbSNP: rs397516208
NCBI 1000 Genomes Browser:
rs397516208
Molecular consequence:
  • NM_000257.4:c.4276G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_126491.1:n.861C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Primary dilated cardiomyopathy (DCM)
Synonyms:
Dilated Cardiomyopathy
Identifiers:
EFO: EFO_0000407; MONDO: MONDO:0005021; MeSH: D002311; MedGen: C0007193; Human Phenotype Ontology: HP:0001644

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000564451ClinGen Cardiomyopathy Variant Curation Expert Panel
reviewed by expert panel

(ClinGen CMP ACMG Specifications v1)		Uncertain significance
(Sep 22, 2021) 		germlinecuration

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

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

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

Details of each submission

From ClinGen Cardiomyopathy Variant Curation Expert Panel, SCV000564451.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (1)

Description

The NM_000257.4 (MYH7): c.4276G>A (p.Glu1426Lys) variant has been identified in 5 individuals with DCM (PS4_Supporting; Villard 2005 PMID: 1576978; Shipman 2011 PMID: 21482996; Vikhorev 2017 PMID: 29093449; GeneDx pers. comm.; LMM pers. comm.), including as a de novo occurrence in 1 infant with an additional variant in a cardiomyopathy-associated gene (GeneDx pers. comm.) and in 1 individual with HCM (Walsh 2017 PMID: 27532257; OMGL pers. comm.). Because of the additional variant observed in the individual with the de novo occurrence, the PM6 criterion was not applied. This variant has also been reported in 1 individual with LVNC and reduced ejection fraction and in 1 individual with familial nondilated cardiomyopathy and their child with LVNC (Ambry pers. comm.; Invitae pers. comm). This variant segregated with disease in 2 affected relatives with DCM from 1 family (Villard 2005 PMID: 1576978); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, due to insufficient evidence, this variant is classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PP3.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 1, 2024