chr14-23417200-G-C

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.4472C>G (p.Ser1491Cys) variant in the MYH7 gene is 0.98% (698/66740) 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/CA015008/MONDO:0004994/002

Frequency

Genomes: 𝑓 0.0085 ( 13 hom., cov: 33)
Exomes 𝑓: 0.012 ( 143 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

1
7
10

Clinical Significance

Benign reviewed by expert panel B:25

Conservation

PhyloP100: 7.79
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]
MHRT (HGNC:51291): (myosin heavy chain associated RNA transcript) This gene encodes a spliced long non-coding RNA that may act as a cardioprotective agent in the heart. Based on a study of a similar gene in mouse, the encoded transcript may regulate chromatin remodeling by acting as a decoy to the BRG1 chromatin repressor complex thus preventing it from binding to its genomic targets. Blocking the actions of BRG1 could be crucial in protecting the heart from pathological hypertrophy. [provided by RefSeq, Dec 2014]

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 rank MANE Protein UniProt
MYH7NM_000257.4 linkc.4472C>G p.Ser1491Cys missense_variant Exon 32 of 40 ENST00000355349.4 NP_000248.2 P12883
MYH7NM_001407004.1 linkc.4472C>G p.Ser1491Cys missense_variant Exon 31 of 39 NP_001393933.1
MHRTNR_126491.1 linkn.652-12G>C intron_variant Intron 4 of 5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYH7ENST00000355349.4 linkc.4472C>G p.Ser1491Cys missense_variant Exon 32 of 40 1 NM_000257.4 ENSP00000347507.3 P12883

Frequencies

GnomAD3 genomes
AF:
0.00854
AC:
1299
AN:
152148
Hom.:
13
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00251
Gnomad AMI
AF:
0.0110
Gnomad AMR
AF:
0.0124
Gnomad ASJ
AF:
0.00115
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00601
Gnomad FIN
AF:
0.00179
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.0135
Gnomad OTH
AF:
0.0105
GnomAD3 exomes
AF:
0.00818
AC:
2058
AN:
251494
Hom.:
16
AF XY:
0.00836
AC XY:
1136
AN XY:
135922
show subpopulations
Gnomad AFR exome
AF:
0.00258
Gnomad AMR exome
AF:
0.00639
Gnomad ASJ exome
AF:
0.00228
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00676
Gnomad FIN exome
AF:
0.00231
Gnomad NFE exome
AF:
0.0128
Gnomad OTH exome
AF:
0.00863
GnomAD4 exome
AF:
0.0119
AC:
17342
AN:
1461892
Hom.:
143
Cov.:
34
AF XY:
0.0117
AC XY:
8506
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.00215
Gnomad4 AMR exome
AF:
0.00704
Gnomad4 ASJ exome
AF:
0.00195
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00715
Gnomad4 FIN exome
AF:
0.00256
Gnomad4 NFE exome
AF:
0.0140
Gnomad4 OTH exome
AF:
0.00929
GnomAD4 genome
AF:
0.00854
AC:
1300
AN:
152266
Hom.:
13
Cov.:
33
AF XY:
0.00786
AC XY:
585
AN XY:
74468
show subpopulations
Gnomad4 AFR
AF:
0.00250
Gnomad4 AMR
AF:
0.0123
Gnomad4 ASJ
AF:
0.00115
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00622
Gnomad4 FIN
AF:
0.00179
Gnomad4 NFE
AF:
0.0135
Gnomad4 OTH
AF:
0.0104
Alfa
AF:
0.0116
Hom.:
6
Bravo
AF:
0.00928
TwinsUK
AF:
0.0129
AC:
48
ALSPAC
AF:
0.0156
AC:
60
ESP6500AA
AF:
0.00295
AC:
13
ESP6500EA
AF:
0.0115
AC:
99
ExAC
AF:
0.00746
AC:
906
Asia WGS
AF:
0.00289
AC:
10
AN:
3478
EpiCase
AF:
0.0133
EpiControl
AF:
0.0139

ClinVar

Significance: Benign
Submissions summary: Benign:25
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not specified Benign:10
Jan 07, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

p.Ser1491Cys in exon 31 of MYH7: This variant is not expected to have clinical s ignificance because it has been identified in 1.1% (698/66740) of European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs3729823). -

Apr 17, 2012
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 12, 2013
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 03, 2019
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 14, 2014
Genetic Services Laboratory, University of Chicago
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:5
Nov 07, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 23, 2018
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

MYH7: BS1, BS2 -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Hypertrophic cardiomyopathy Benign:3
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 10, 2022
Cohesion Phenomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 24, 2013
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: research

- -

Cardiomyopathy Benign:2
Dec 15, 2016
ClinGen Cardiomyopathy Variant Curation Expert Panel
Significance: Benign
Review Status: reviewed by expert panel
Collection Method: curation

The filtering allele frequency of the c.4472C>G (p.Ser1491Cys) variant in the MYH7 gene is 0.98% (698/66740) 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). -

Mar 05, 2018
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 1 Benign:2
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Apr 12, 2015
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dilated cardiomyopathy 1S Benign:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Hypertrophic cardiomyopathy;C0007196:Restrictive cardiomyopathy;C0878544:Cardiomyopathy Benign:1
Nov 14, 2018
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1
Jul 21, 2015
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.23
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.74
D
Eigen
Uncertain
0.24
Eigen_PC
Uncertain
0.39
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.85
D
MetaRNN
Benign
0.011
T
MetaSVM
Benign
-0.29
T
MutationAssessor
Uncertain
2.6
M
PrimateAI
Uncertain
0.75
T
PROVEAN
Benign
-2.1
N
REVEL
Uncertain
0.40
Sift
Benign
0.035
D
Sift4G
Benign
0.16
T
Polyphen
0.0070
B
Vest4
0.56
MVP
0.94
MPC
0.89
ClinPred
0.044
T
GERP RS
5.3
Varity_R
0.34
gMVP
0.86

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.

Other links and lift over

dbSNP: rs3729823; hg19: chr14-23886409; API