chr14-23423701-A-G

Position:

chr14-23423701-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.2945T>C (p.Met982Thr) variant in the MYH7 gene is 0.11% (88/66740) of European chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). LINK:https://erepo.genome.network/evrepo/ui/classification/CA013227/MONDO:0004994/002

Frequency

Genomes: 𝑓 0.00093 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 6 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:3B:19

Conservation

PhyloP100: 9.09

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.2945T>C	p.Met982Thr	missense_variant	24/40	ENST00000355349.4	NP_000248.2	P12883
MYH7	NM_001407004.1 linkuse as main transcript	c.2945T>C	p.Met982Thr	missense_variant	23/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.2945T>C	p.Met982Thr	missense_variant	24/40	1	NM_000257.4	ENSP00000347507.3		P12883

Frequencies

GnomAD3 genomes

AF:

0.000927

AC:

141

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.000850

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00159

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.000839

AC:

211

AN:

251492

Hom.:

AF XY:

0.000809

AC XY:

110

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.00142

Gnomad OTH exome

AF:

0.000977

GnomAD4 exome

AF:

0.00174

AC:

2545

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

1196

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000545

Gnomad4 FIN exome

AF:

0.000431

Gnomad4 NFE exome

AF:

0.00215

Gnomad4 OTH exome

AF:

0.00118

GnomAD4 genome

AF:

0.000927

AC:

141

AN:

152158

Hom.:

Cov.:

AF XY:

0.000753

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.000850

Gnomad4 NFE

AF:

0.00159

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.00149

Hom.:

Bravo

AF:

0.000888

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.000906

AC:

110

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00147

EpiControl

AF:

0.00166

ClinVar

Significance: Benign

Submissions summary: Uncertain:3Benign:19

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 11, 2024	proposed classification - variant undergoing re-assessment, contact laboratory -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 28, 2020	Variant summary: MYH7 c.2945T>C (p.Met982Thr) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00085 in 253160 control chromosomes, predominantly at a frequency of 0.0014 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is slightly higher than (approximately 1.12-fold) the estimated maximal expected allele frequency for a pathogenic variant in MYH7 causing Cardiomyopathy phenotype (0.0013), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2945T>C has been reported in the literature in individuals affected with Cardiomyopathy, but also in controls, including in one family where the variant did not segregate with disease (e.g. Clemente_2017). Furthermore, the variant has been reported in multiple affected individuals that carried other pathogenic variants, including MYBPC3 c.1504C>T, p.Arg502Trp; MYBPC3 c.2157_2158delTG, p.Cys719X; MYBPC3, p.Val219Phe, providing supporting evidence for a benign role (e.g. Millat_Clinica Chimica Acta_2010, Millat_EJMG_2010, Ho_2010). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 11 other ClinVar submitters (evaluation after 2014) cite the variant with conflicting assessments (uncertain significance, n=2; benign/likely benign, n=9). Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2019	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Feb 11, 2015	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Met982Thr (c.2945 T>C) in the MYH7 gene [NM_00257.2]. This variant has been reported in at least three individuals with HCM (two of which had an additional sarcomeric variant identified), 2-3 unrelated individuals with abnormal echocardiograms ascertained in the Framingham study, two individuals with DCM, and multiple individuals tested for cardiomyopathy at the testing lab (many with another variant considered pathogenic). Millat et al (2010) observed p.Met982Thr in two unrelated individuals with HCM, however, both of them had an additional variant in a sarcomere gene so the authors noted they could not rule out this variant as a rare benign variant. Morita et al (2006) looked for variants in genes associate with cardiomyopathy in individuals from the Framingham Heart Study who had LVWT > 13 mm and did not have hypertension. They observed p.Met982Thr in one of those individuals. Of note, they only found sarcomeric variants in 16% of this sample, this is lower than the ~40% yield that would be expected with the genes they examined and a sample of HCM patients. This would suggest that many individuals in this sample do not truly have HCM. They then looked for the variants they had identified in the first sample in a randomly collected sample of the Framingham Heart Study Offspring participants and identified p.Met982Thr in two reportedly unrelated individuals (unclear if one of them could be related to the first individual). The authors reported that one individual had an echocardiographic pattern consistent with "burnt out" cardiac hypertrophy with a dilated left ventricle (LV diastolic diameter >56 mm) and enlarged atrium, whereas the other had a mildly enlarged left atrium and ECG voltages suggestive of HCM. Both individuals were reported to normotensive. Mestroni et al (2010) in an ACC poster abstract reported this mutation in one individual with dilated cardiomyopathy from a DCM registry comprised of patients from Italy and the US. I also found a poster online from a German group that reported the variant in a patient with DCM (Waldmuller et al; their cohort seems to unique from the Mestroni et al cohort). In addition, I found a Spanish language online publication that appears to report the variant in an individual with HCM. Finally, this variant was identified in a recent paper from Gruner et al. 2011 in a patient with apical HCM. In this study, the authors screened 429 HCM probands for mutations in one of eleven genes associated with HCM (their panel included 8 sarcomere protein genes and 3 other genes (GLA, PRKAG2, and LAMP2)). This particular variant was identified in a male with apical HCM diagnosed at 18 years of age. The authors do not provide any specific details about the variant or control data. This proband reportedly had a family history of HCM; however the authors provided no specific details or segregation analysis, and defined “family history” as either documented evidence of HCM or by “highly convincing patient report”. No other variants have been reported in association with cardiomyopathy at codon 982 or nearby residues. The change is chemically non-conservative from a non-polar amino acid to a polar amino acid. The methionine at residue 982 is completely conserved across species, as are neighboring amino acids. In terms of in silico analysis, Polyphen predicts this variant to be probably damaging and Mutation Taster predicts this variant to be disease causing. In total, this particular variant has been seen in 22 of 7,003 published controls, laboratory controls, and publically available general population datasets. Morita et al. (2006) did not identify the variant in 300 presumably healthy co -

not provided

Uncertain:1Benign:2

Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Feb 03, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	MYH7: PP3, BS2 -

Cardiomyopathy

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 20, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 11, 2018	- -
Benign, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Dec 15, 2016	The filtering allele frequency of the c.2945T>C (p.Met982Thr) variant in the MYH7 gene is 0.11% (88/66740) of European chromosomes by the Exome Aggregation Consortium (http://exac.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; PMID:29300372). -

Increased left ventricular wall thickness

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Hypertrophic cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

MYH7-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 11, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Dilated cardiomyopathy 1S

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 19, 2019

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

MYH7-related skeletal myopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 19, 2019

Myosin storage myopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 19, 2019

Dilated Cardiomyopathy, Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 30, 2021

- -

Left ventricular noncompaction

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jun 21, 2020

we reviewed this variant Benign in 2020, because of BA1 -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hypertrophic cardiomyopathy 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 19, 2019

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

CardioboostCm

Pathogenic

0.96

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.41

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.84

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.75

M_CAP

Pathogenic

0.96

MetaRNN

Uncertain

0.71

MetaSVM

Pathogenic

0.93

MutationAssessor

Uncertain

2.8

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-4.2

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.027

Polyphen

0.98

Vest4

0.97

MVP

0.98

MPC

1.2

ClinPred

0.049

GERP RS

5.1

Varity_R

0.71

gMVP

0.99

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over