14-23413809-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS4_ModeratePS2PM2PP3

This summary comes from the ClinGen Evidence Repository: 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 LINK:https://erepo.genome.network/evrepo/ui/classification/CA016441/MONDO:0005021/002

Frequency

Genomes: not found (cov: 33)

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:7O:1

Conservation

PhyloP100: 6.06

Publications

13 publications found

Variant links:

Genes affected

MYH7 (HGNC:7577): (myosin heavy chain 7) Muscle myosin is a hexameric protein containing 2 heavy chain subunits, 2 alkali light chain subunits, and 2 regulatory light chain subunits. This gene encodes the beta (or slow) heavy chain subunit of cardiac myosin. It is expressed predominantly in normal human ventricle. It is also expressed in skeletal muscle tissues rich in slow-twitch type I muscle fibers. Changes in the relative abundance of this protein and the alpha (or fast) heavy subunit of cardiac myosin correlate with the contractile velocity of cardiac muscle. Its expression is also altered during thyroid hormone depletion and hemodynamic overloading. Mutations in this gene are associated with familial hypertrophic cardiomyopathy, myosin storage myopathy, dilated cardiomyopathy, and Laing distal myopathy. [provided by RefSeq, May 2022]

MYH7 Gene-Disease associations (from GenCC):

dilated cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
dilated cardiomyopathy 1S
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
hypertrophic cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hypertrophic cardiomyopathy 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
MYH7-related skeletal myopathy
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
myopathy, myosin storage, autosomal recessive
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
myopathy, myosin storage, autosomal dominant
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
congenital myopathy 7A, myosin storage, autosomal dominant
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Ebstein anomaly
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hyaline body myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
left ventricular noncompaction
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
congenital heart disease
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

MYH7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PS2

For more information check the summary or visit ClinGen Evidence Repository.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4 link	c.5740G>A	p.Glu1914Lys	missense_variant	Exon 39 of 40	ENST00000355349.4	NP_000248.2	P12883
MYH7	NM_001407004.1 link	c.5740G>A	p.Glu1914Lys	missense_variant	Exon 38 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYH7	ENST00000355349.4 link	c.5740G>A	p.Glu1914Lys	missense_variant	Exon 39 of 40	1	NM_000257.4	ENSP00000347507.3	P12883
MYH7	ENST00000713768.1 link	c.5740G>A	p.Glu1914Lys	missense_variant	Exon 39 of 41			ENSP00000519070.1
MYH7	ENST00000713769.1 link	c.5740G>A	p.Glu1914Lys	missense_variant	Exon 38 of 39			ENSP00000519071.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Primary dilated cardiomyopathy

Pathogenic:2

Jan 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Mar 22, 2021

ClinGen Cardiomyopathy Variant Curation Expert Panel

Significance:Likely pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

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 -

Dilated cardiomyopathy 1S

Pathogenic:1

Feb 19, 2020

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Cardiomyopathy

Pathogenic:1

Mar 18, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1S;C4552004:MYH7-related skeletal myopathy

Pathogenic:1

Jan 01, 2013

Neurogenetics Laboratory, Royal Perth Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYH7: PS4, PM1, PM2, PP2, PP3 -

Hypertrophic cardiomyopathy

Pathogenic:1

May 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1914 of the MYH7 protein (p.Glu1914Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy, hypertrophic cardiomyopathy, and/or additional features of skeletal myopathy (PMID: 22464770, 24664454, 27532257, 28855170, 30996762). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 43088). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

MYH7-related skeletal myopathy

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Associated with cardiac transplant at age 3 and 3.5 yrs -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

CardioboostCm

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.90

MetaSVM

Pathogenic

0.85

MutationAssessor

Pathogenic

4.0

PhyloP100

6.1

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-2.8

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.020

Polyphen

1.0

Vest4

0.77

MutPred

0.67

Gain of ubiquitination at E1914 (P = 0.0031);

MVP

0.99

MPC

1.2

ClinPred

1.0

GERP RS

5.6

Varity_R

0.65

gMVP

0.99

Mutation Taster

=12/88

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over