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NM_000257.4(MYH7):c.5740G>A (p.Glu1914Lys) AND Primary dilated 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:
RCV000035983.15

Allele description [Variation Report for NM_000257.4(MYH7):c.5740G>A (p.Glu1914Lys)]

NM_000257.4(MYH7):c.5740G>A (p.Glu1914Lys)

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.5740G>A (p.Glu1914Lys)
Other names:
NM_000257.3(MYH7):c.5740G>A; NM_000257.4(MYH7):c.5740G>A
HGVS:
  • NC_000014.9:g.23413809C>T
  • NG_007884.1:g.26853G>A
  • NM_000257.4:c.5740G>AMANE SELECT
  • NP_000248.2:p.Glu1914Lys
  • NP_000248.2:p.Glu1914Lys
  • LRG_384t1:c.5740G>A
  • LRG_384:g.26853G>A
  • NC_000014.8:g.23883018C>T
  • NM_000257.2:c.5740G>A
  • NM_000257.3:c.5740G>A
  • c.5740G>A
Protein change:
E1914K
Links:
dbSNP: rs397516254
NCBI 1000 Genomes Browser:
rs397516254
Molecular consequence:
  • NM_000257.4:c.5740G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
2

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

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000059635Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)
Pathogenic
(Jan 29, 2016)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV000564463ClinGen Cardiomyopathy Variant Curation Expert Panel
reviewed by expert panel

(ClinGen CMP ACMG Specifications v1)
Likely pathogenic
(Mar 22, 2021)
germlinecuration

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration
not providedgermlinenot provided22not providednot providednot providedclinical testing

Citations

PubMed

The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing.

Pugh TJ, Kelly MA, Gowrisankar S, Hynes E, Seidman MA, Baxter SM, Bowser M, Harrison B, Aaron D, Mahanta LM, Lakdawala NK, McDermott G, White ET, Rehm HL, Lebo M, Funke BH.

Genet Med. 2014 Aug;16(8):601-8. doi: 10.1038/gim.2013.204. Epub 2014 Feb 6.

PubMed [citation]
PMID:
24503780

Genetic testing for dilated cardiomyopathy in clinical practice.

Lakdawala NK, Funke BH, Baxter S, Cirino AL, Roberts AE, Judge DP, Johnson N, Mendelsohn NJ, Morel C, Care M, Chung WK, Jones C, Psychogios A, Duffy E, Rehm HL, White E, Seidman JG, Seidman CE, Ho CY.

J Card Fail. 2012 Apr;18(4):296-303. doi: 10.1016/j.cardfail.2012.01.013. Epub 2012 Feb 15.

PubMed [citation]
PMID:
22464770
PMCID:
PMC3666099
See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059635.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (4)

Description

The p.Glu1914Lys variant in MYH7 has been previously identified in 3 individuals with childhood onset of DCM and was de novo in two of them with parental relati onships confirmed (Lakdawala 2012, Lamont 2014, Pugh 2014). It was absent from l arge population studies. This variant was predicted to be pathogenic using a com putational tool clinically validated by our laboratory. This tool's pathogenic p rediction is estimated to be correct 94% of the time (Jordan 2011). In summary, this variant meets our criteria to be classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided2not provided2not provided

From ClinGen Cardiomyopathy Variant Curation Expert Panel, SCV000564463.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (3)

Description

The c.5740G>A (p.Glu1914Lys) variant in MYH7 has been reported in at least 6 individuals with complex cardiomyopathy presentations, including predominantly dilated cardiomyopathy, features of LVNC, and restrictive physiology with early-onset in multiple instances (Lakdawala 2012 PMID: 22464770; Pugh 2014 PMID: 24503780; Lamont 2015 PMID: 20301606; Walsh 2017 PMID: 27532257; Wang 2017 PMID: 28855170; Miura 2019 PMID: 30996762). This variant segregated with disease in 2 affected siblings from 1 family (Miura 2019 PMID: 30996762); however this data is currently insufficient to apply PP1. This variant has been confirmed de novo occurrence in 2 of the above reported individuals with additional features of myopathy (PS2; Lamont 2014 PMID24664454). This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org, v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PS2; PM2; PP3

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

Last Updated: Jul 7, 2024