rs45478699

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. BS1PP3

This summary comes from the ClinGen Evidence Repository: The c.3286G>T (p.Asp1096Tyr) variant in MYH7 has been identified in 0.023% (FAF 95% CI; 40/129162) of European chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; Kelly 2018 PMID:29300372). Allowing a variant to reach a likely benign classification based on BS1 alone represents a revision of the original ACMG/AMP framework by ClinGen’s Sequence Variant Interpretation Working Group (Tavtigian 2018 PMID:29300386). Additionally, while computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3), this pathogenic evidence code (PP3) was not considered to be in conflict with a likely benign conclusion given the accuracy of computation prediction tools. In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PP3, BS1 LINK:https://erepo.genome.network/evrepo/ui/classification/CA013546/MONDO:0004994/002

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel P:1U:15B:6

Conservation

PhyloP100: 7.61

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

BS1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.3286G>T	p.Asp1096Tyr	missense_variant	26/40	ENST00000355349.4
MYH7	NM_001407004.1 linkuse as main transcript	c.3286G>T	p.Asp1096Tyr	missense_variant	25/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.3286G>T	p.Asp1096Tyr	missense_variant	26/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000147

AC:

AN:

251448

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

135898

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:

0.000325

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000123

AC:

180

AN:

1460514

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

100

AN XY:

726572

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000153

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000131

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000181

Hom.:

Bravo

AF:

0.000128

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000356

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1Uncertain:15Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:5Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The MYH7 p.Asp1096Tyr variant was identified in 4 of 1006 proband chromosomes (frequency: 0.00398) from individuals with dilated cardiomyopathy (DCM) or left ventricular non-compaction (LVNC) and was not identified in 506 control chromosomes from healthy individuals (Hershberger_2008_PMID:19412328; Miszalski-Jamka_2017_PMID:28798025). The variant was identified in dbSNP (ID: rs45478699) and ClinVar (classified as uncertain significance by Invitae, Laboratory for Molecular Medicine, ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel and five other laboratories, and classified as likely pathogenic by CSER_CC_NCGL; University of Washington Medical Center). The variant was identified in control databases in 40 of 282846 chromosomes at a frequency of 0.0001414 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the European (non-Finnish) population in 40 of 129162 chromosomes (freq: 0.00031), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Asp1096 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2021	This variant is associated with the following publications: (PMID: 23299917, 25163546, 32659924, 22337857, 23403236, 18555187, 27247418, 25031304, 19412328, 26383716, 27688314, 29300372, 28798025, 31737537, 28588093, 32528171, 32880476) -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 29, 2023	- -

Cardiomyopathy

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Oct 30, 2019	- -
Likely benign, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Mar 22, 2021	The c.3286G>T (p.Asp1096Tyr) variant in MYH7 has been identified in 0.023% (FAF 95% CI; 40/129162) of European chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; Kelly 2018 PMID:29300372). Allowing a variant to reach a likely benign classification based on BS1 alone represents a revision of the original ACMG/AMP framework by ClinGen’s Sequence Variant Interpretation Working Group (Tavtigian 2018 PMID: 29300386). Additionally, while computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3), this pathogenic evidence code (PP3) was not considered to be in conflict with a likely benign conclusion given the accuracy of computation prediction tools. In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PP3, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 30, 2023	This missense variant replaces aspartic acid with tyrosine at codon 1096 of the MYH7 protein. Computational prediction suggests that this variant may have 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 several individuals affected with cardiomyopathy (PMID: 19412328, 27247418, 25031304, 32659924, 32746648, 32880476). This variant has also been identified in 40/282846 chromosomes (40/129122 non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Although the variant allele frequency is greater than expected for MYH7-related disorders based on prevalence, penetrance, and allelic heterogeneity, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces aspartic acid with tyrosine at codon 1096 of the MYH7 protein. Computational prediction suggests that this variant may have 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 several individuals affected with cardiomyopathy (PMID: 19412328, 27247418, 25031304, 32659924, 32746648, 32880476). This variant has also been identified in 40/282846 chromosomes (40/129122 non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Although the variant allele frequency is greater than expected for MYH7-related disorders based on prevalence, penetrance, and allelic heterogeneity, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Dilated cardiomyopathy 1S

Uncertain:2Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 21, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Uncertain significance, no assertion criteria provided	clinical testing	Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen	May 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

Primary dilated cardiomyopathy

Pathogenic:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2022	The p.Asp1096Tyr variant in MYH7 has been previously reported in >3 individuals with DCM left ventricular hypertrophy (Hershberger 2008 PMID: 19412328, Helms 2014 PMID: 25031304, LMM data). This variant has also been identified in 0.026% (18/68042) European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Likely Benign on Mar 22, 2021 by the ClinGen-approved Cardiomyopathy variant curation expert panel (Variation ID 42953). Given the frequency, this variant is classified as likely benign. ACMG/AMP Criteria applied: BS1, PP3. -
Likely pathogenic, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Oct 01, 2016	Found in patient having exome sequencing for an unrelated indication. No known history of dilated cardiomyopathy. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. -

Myosin storage myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 21, 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

See cases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Nov 17, 2020

We observed a genetic variant c.3286G>T (p.D1096Y) in a male 68-y.o. patient diagnosed with left ventricular non-compaction and heart rhythm disorders. The p.D1096Y variant has a frequency of 1.414e-4 in gnomAD. The variant was detected in a MYH7 gene with z-score of 3.93, therefore intolerant to missense variants. Online in silico tools (PolyPhen2, MutationTaster, SIFT) predict the variant to be deleterious. However, in the absence of family screening results and the data on functional effects, we could only classify the p.D1096Y variant as the variant of uncertain clinical significance. -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 1096 of the MYH7 protein (p.Asp1096Tyr). This variant is present in population databases (rs45478699, gnomAD 0.03%). This missense change has been observed in individual(s) with cardiomyopathy (PMID: 19412328, 25031304, 25163446, 27247418, 28798025, 29300372). ClinVar contains an entry for this variant (Variation ID: 42953). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

MYH7-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 06, 2023

The MYH7 c.3286G>T variant is predicted to result in the amino acid substitution p.Asp1096Tyr. This variant has been reported in individuals with dilated cardiomyopathy (Hershberger et al. 2008. PubMed ID: 19412328, Table 2), individuals with hypertrophic cardiomyopathy (Table S2 - Helms et al. 2014. PubMed ID: 25031304; Dataset S1 - Homburger. 2016. PubMed ID: 27247418), and an individual with left ventricular noncompaction (Table S3 - Miszalski-Jamka et al. 2017. PubMed ID: 28798025). However, it has also been reported in presumably healthy controls (Andreasen et al. 2013. PubMed ID: 23299917; Dataset S1 - Homburger. 2016. PubMed ID: 27247418). This variant is reported in 0.031% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-23890217-C-A). In ClinVar, this variant has conflicting interpretations of pathogenicity ranging from benign to uncertain including likely benign by an expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/42953/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hypertrophic cardiomyopathy 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Jul 30, 2015

The Asp1096Tyr variant in MYH7 has been previously reported by Hershberger et al (2008) in 2 DCM probands. Helms et al (2014) analysed sarcomere transcript and protein levels in septal myectomy and transplant specimens from genotyped HCM patients - one of whome carried this MYH Asp1096Tyr variant. This variant has been reported with an allele frequency of 0.0001 (18/66,720 European non-Finnish alleles and 1/908 'other') in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). The MYH7 Asp1096Tyr variant occurs in a conserved region, and in-silico tools (SIFT, PolyPhen, MutationTaster and CADD) support a damaging role for this variant, however this alone is not strong evidence for pathogenicity. We have identified this variant in 1 HCM proband who presented in her 30's with asymmetric hypertrophy (IVS 21mm) and obstruction. This proband experienced a sudden cardiac death in her 50s. It is noted that this proband also carried a pathogenic MYBPC3 nonsense variant. Based on the limited reports in the literature, and our finding of MYH7 Asp1096Tyr in an isolated HCM case who carried an additional variant which is known to be disease-causing, we have classified this variant as having "uncertain significance". Additional evidence is required to fully establish its pathogenic role. -

MYH7-related skeletal myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 21, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

CardioboostCm

Benign

0.061

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.73

MetaRNN

Pathogenic

0.94

MetaSVM

Pathogenic

0.85

MutationAssessor

Pathogenic

3.3

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-6.8

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.85

MVP

0.99

MPC

1.3

ClinPred

0.80

GERP RS

5.5

Varity_R

0.84

gMVP

0.95

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