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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hypertrophic cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hypertrophic cardiomyopathy 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
MYH7-related skeletal myopathy
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000257.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	NM_000257.4	MANE Select	c.5740G>A	p.Glu1914Lys	missense	Exon 39 of 40	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.5740G>A	p.Glu1914Lys	missense	Exon 38 of 39	NP_001393933.1	P12883

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYH7	ENST00000355349.4	TSL:1 MANE Select	c.5740G>A	p.Glu1914Lys	missense	Exon 39 of 40	ENSP00000347507.3	P12883
MYH7	ENST00000858540.1		c.5785G>A	p.Glu1929Lys	missense	Exon 39 of 40	ENSP00000528599.1
MYH7	ENST00000965955.1		c.5785G>A	p.Glu1929Lys	missense	Exon 39 of 40	ENSP00000636014.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary dilated cardiomyopathy (2)

Cardiomyopathy (1)

Dilated cardiomyopathy 1S (1)

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

Hypertrophic cardiomyopathy (1)

not provided (1)

MYH7-related skeletal myopathy (1)

Computational scores

Source: dbNSFP v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over