rs397516179

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS4PM2PP3

This summary comes from the ClinGen Evidence Repository: The NM_000257.4(MYH7):c.3169G>A (p.Gly1057Ser) variant has been identified in >20 individuals with HCM, including 1 individual with an additional variant in another gene that may contribute to their disease and 2 individuals with DCM (PS4; Van Driest 2004 PMID 15358028; Kapplinger 2014 PMID:24510615, Walsh 2017 PMID:27532257; Hazebroek 2018 PMID:24510615; Ho 2018 PMID:30297972; van Lint 2019 PMID:30847666; Robyns 2020 PMID:31513939; Verdonschot 2020 PMID:32880476; Ambry pers. comm; ARUP pers. comm; GeneDx pers. comm.; Invitae pers. comm; LMM pers. comm.). Additionally, this variant has also been reported in 1 individual with RCM and AFib, 4 individuals with unspecified heart disease or cardiomyopathy and 1 individual with LVH, CHD and trisomy 21 (Ambry pers. comm.; GeneDx pers. comm., Invitae pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). 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 hypertrophic cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4, PM2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA013436/MONDO:0005045/002

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:8U:2

Conservation

PhyloP100: 7.76

Publications

7 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:

ENSG00000294572 (HGNC:):

ENSG00000294572 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

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.3169G>A	p.Gly1057Ser	missense_variant	Exon 25 of 40	ENST00000355349.4	NP_000248.2	P12883
MYH7	NM_001407004.1 link	c.3169G>A	p.Gly1057Ser	missense_variant	Exon 24 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYH7	ENST00000355349.4 link	c.3169G>A	p.Gly1057Ser	missense_variant	Exon 25 of 40	1	NM_000257.4	ENSP00000347507.3	P12883
MYH7	ENST00000713768.1 link	c.3169G>A	p.Gly1057Ser	missense_variant	Exon 25 of 41			ENSP00000519070.1
MYH7	ENST00000713769.1 link	c.3169G>A	p.Gly1057Ser	missense_variant	Exon 24 of 39			ENSP00000519071.1
ENSG00000294572	ENST00000724465.1 link	n.139C>T		non_coding_transcript_exon_variant	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000795

AC:

AN:

251486

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461814

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1111978

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41408

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000296

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:8Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:4Uncertain:1

Feb 09, 2017

Center for Human Genetics, University of Leuven

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG score unknown significance -

Feb 24, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Gly1057Ser variant in MYH7 has been identified in >20 individuals with hypertrophic cardiomyopathy (HCM), including 1 individual with an additional variant in another gene that may contribute to their disease and in 2 individuals with DCM (Van Driest 2004 PMID: 15358028; Kapplinger 2014 PMID: 24510615, Walsh 2017 PMID: 27532257; Hazebroek 2018 PMID: 29540472; Ho 2018 PMID: 30297972; van Lint 2019 PMID: 30847666; Robyns 2020 PMID: 31513939; Verdonschot 2020 PMID: 32880476; Ambry pers. comm; ARUP pers. comm; GeneDx pers. comm.; Invitae pers. comm; LMM pers. comm.). This variant was absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In addition, this variant was classified as likely pathogenic on Feb 25, 2019 by the ClinGen Cardiomyopathy Variant Curation Expert Panel (ClinVar Variation ID: 42950). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PP3. -

Dec 09, 2021

ClinGen Cardiomyopathy Variant Curation Expert Panel

Significance:Likely pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000257.4(MYH7):c.3169G>A (p.Gly1057Ser) variant has been identified in >20 individuals with HCM, including 1 individual with an additional variant in another gene that may contribute to their disease and 2 individuals with DCM (PS4; Van Driest 2004 PMID 15358028; Kapplinger 2014 PMID:24510615, Walsh 2017 PMID:27532257; Hazebroek 2018 PMID:24510615; Ho 2018 PMID: 30297972; van Lint 2019 PMID: 30847666; Robyns 2020 PMID: 31513939; Verdonschot 2020 PMID: 32880476; Ambry pers. comm; ARUP pers. comm; GeneDx pers. comm.; Invitae pers. comm; LMM pers. comm.). Additionally, this variant has also been reported in 1 individual with RCM and AFib, 4 individuals with unspecified heart disease or cardiomyopathy and 1 individual with LVH, CHD and trisomy 21 (Ambry pers. comm.; GeneDx pers. comm., Invitae pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). 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 hypertrophic cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4, PM2, PP3. -

Mar 24, 2024

All of Us Research Program, National Institutes of Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces glycine with serine at codon 1057 in the neck and hinge domain (S2) domain of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over ten unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 27476098, 27532257, 30847666, 31568572, 33029862, 33495596, Kaam et al. 2019, doi: 10.1038/s41431-019-0404-7, ClinVar SCV000564443.5) or suspected of having hypertrophic cardiomyopathy (PMID: 24510615). This variant has been identified in 2/251486 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1057 of the MYH7 protein (p.Gly1057Ser). This variant is present in population databases (rs397516179, gnomAD 0.002%). This missense change has been observed in individuals with hypertrophic cardiomyopathy and/or MYH7-related conditions (PMID: 15358028, 27532257, 29255176, 30297972, 30847666, 31513939; internal data). ClinVar contains an entry for this variant (Variation ID: 42950). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. This variant disrupts the p.Gly1057 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been observed in individuals with MYH7-related conditions (PMID: 29398688), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2Uncertain:1

Oct 01, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15358028, 27532257, 24510615, 21310275, 29300372, 29540472, 31513939, 32894683, 30297972, 34542152, 31568572, 30847666, 16199542, 32880476, 29255176, 37652022, 27476098, 33029862, 33495596) -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYH7: PS4, PM2, PM5:Supporting, PP3 -

Nov 05, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Pathogenic:1

May 06, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces glycine with serine at codon 1057 in the neck and hinge domain (S2) domain of the MYH7 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over ten unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 27476098, 27532257, 30297972, 30847666, 31568572, 33029862, 33495596; DOI:10.1038/s41431-019-0404-7) or suspected to be affected with hypertrophic cardiomyopathy (PMID: 24510615). It has also been reported in one individual affected with dilated cardiomyopathy (PMID: 37198425). This variant has been identified in 2/251486 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Sep 06, 2024

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G1057S variant (also known as c.3169G>A), located in coding exon 23 of the MYH7 gene, results from a G to A substitution at nucleotide position 3169. The glycine at codon 1057 is replaced by serine, an amino acid with similar properties. This variant has been identified in multiple individuals with hypertrophic cardiomyopathy (HCM) (Van Driest SL et al. J. Am Coll Cardiol 2004 Aug; 44(3):602-10; Kapplinger JD et al. J Cardiovasc Transl Res 2014 Apr; 7(3):347-61; Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Hazebroek MR et al. Circ Heart Fail. 2018;11:e004682; Ambry internal data). In one family with HCM, this variant was seen in two affected relatives and one unaffected relative (Robyns T et al. Eur J Hum Genet. 2017;25(12):1313-1323). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

CardioboostCm

Uncertain

0.87

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.6

PhyloP100

7.8

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-4.5

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

Sift4G

Benign

0.081

Polyphen

1.0

Vest4

0.93

MVP

0.99

MPC

1.1

ClinPred

0.99

GERP RS

4.6

Varity_R

0.55

gMVP

0.73

Mutation Taster

=0/100

disease causing

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over