rs397516179

Positions:

chr14-23422256-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3PS4

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

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 Likely_pathogenic. Variant got 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/exons	MANE	Protein	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.3169G>A	p.Gly1057Ser	missense_variant	25/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1 linkuse as main transcript	c.3169G>A	p.Gly1057Ser	missense_variant	24/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.3169G>A	p.Gly1057Ser	missense_variant	25/40	1	NM_000257.4	ENSP00000347507	P1

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

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251486

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135920

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000324

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 24, 2022	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 20, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Feb 09, 2017	ACMG score unknown significance -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Dec 09, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 04, 2023	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 MYH7-related conditions (PMID: 15358028, 27532257, 29255176, 30297972, 30847666, 31513939; Invitae). ClinVar contains an entry for this variant (Variation ID: 42950). 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%. 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

Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Nov 05, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	MYH7: PS4, PM2, PM5:Supporting, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2024	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) -

Cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 05, 2023

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. 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). 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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2023

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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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

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

MutationTaster

Benign

1.0

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

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