rs727503254

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PS4_SupportingPP1_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000257.4(MYH7):c.2678C>T (p.Ala893Val) variant in MYH7 has been reported in 4 individuals with DCM (PS4_Supporting; Lakdawala 2012 PMID:22464770; Miller 2013 PMID:23054336; LMM pers. comm.). This variant segregated with disease in 5 affected individuals with DCM in 2 families (PP1_Moderate; Lakdawala 2012 PMID:22464770; LMM pers. comm.); however, in one of these families the variant was absent from a set of identical twins with mild LV dysfunction prior to testing at 4 months of age and additional clinical data was not available. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and while missense variants in this region are statistically more likely to be associated with HCM (Walsh 2017 PMID:27532257), location in this region cannot be used to support pathogenicity for other phenotypes; therefore PM1 is not applicable. In addition, computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient and conflicting evidence, this variant is classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting; PM5_Moderate, PM2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA012811/MONDO:0005021/002

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense, splice_region

Scores

Splicing: ADA: 0.9970

Clinical Significance

Uncertain significance reviewed by expert panel P:6U:3

Conservation

PhyloP100: 9.47

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 Uncertain_significance. Variant got 5 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.

PP1

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.2678C>T	p.Ala893Val	missense_variant, splice_region_variant	22/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1 linkuse as main transcript	c.2678C>T	p.Ala893Val	missense_variant, splice_region_variant	21/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.2678C>T	p.Ala893Val	missense_variant, splice_region_variant	22/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461802

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727208

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:6Uncertain:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2023	Reported in association with dilated cardiomyopathy (DCM) in the published literature (Lakdawala et al., 2012; Miller et al., 2013; Pugh et al., 2014; Kelly et al., 2018); Not observed 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: 23074334, 29447731, 34935411, 27532257, 29300372, 22464770, 24503780, 23054336) -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Primary dilated cardiomyopathy

Pathogenic:1Uncertain:1

Uncertain significance, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Sep 22, 2021	The NM_000257.4(MYH7):c.2678C>T (p.Ala893Val) variant in MYH7 has been reported in 4 individuals with DCM (PS4_Supporting; Lakdawala 2012 PMID:22464770; Miller 2013 PMID:23054336; LMM pers. comm.). This variant segregated with disease in 5 affected individuals with DCM in 2 families (PP1_Moderate; Lakdawala 2012 PMID:22464770; LMM pers. comm.); however, in one of these families the variant was absent from a set of identical twins with mild LV dysfunction prior to testing at 4 months of age and additional clinical data was not available. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and while missense variants in this region are statistically more likely to be associated with HCM (Walsh 2017 PMID:27532257), location in this region cannot be used to support pathogenicity for other phenotypes; therefore PM1 is not applicable. In addition, computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient and conflicting evidence, this variant is classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting; PM5_Moderate, PM2. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 14, 2019	The p.Ala893Val variant in MYH7 has been reported in 4 individuals with DCM and segregated with disease in 5 affected relatives from 3 families (Lakdawala 2012, Miller 2013, LMM data). It was absent from large population studies. Computational prediction tools suggest that this variant may not impact protein function although this is not predictive enough to rule out pathogenicity. Of note, this variant lies in the head region of the protein. Missense variants in this region are significantly more likely to cause disease (Walsh 2016). This variant has been classified as likely pathogenic on December 15, 2016 by the ClinGen-approved Inherited Cardiomyopathy expert panel (ClinVar variation ID: 177763). In summary, although additional studies are required to fully establish its clinical significance, the p.Ala893Val variant is likely pathogenic. ACMG/AMP Criteria applied: PM1, PM2, PP1_Moderate, PS4_ Supporting. -

Cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

May 16, 2023

- -

Hypertrophic cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 893 of the MYH7 protein (p.Ala893Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with noncompaction cardiomyopathy and dilated cardiomyopathy (PMID: 22464770, 23054336, 27532257, 29300372, 29447731, 34935411; Invitae). ClinVar contains an entry for this variant (Variation ID: 177763). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 11, 2022

The p.A893V variant (also known as c.2678C>T), located in coding exon 20 of the MYH7 gene, results from a C to T substitution at nucleotide position 2678. The alanine at codon 893 is replaced by valine, an amino acid with similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This variant was reported in a family with dilated cardiomyopathy (DCM), including three affected individuals and two young children who were asymptomatic at the time of evaluation (Lakdawala NK et al. J Card Fail, 2012 Apr;18:296-303; Lakdawala NK et al. Circ Cardiovasc Genet, 2012 Oct;5:503-10). This variant has also been reported in other DCM cohorts; however, clinical details were limited, and some individuals also had variants in other cardiac-related genes (Pugh TJ et al. Genet Med, 2014 Aug;16:601-8; Miller EM et al. J Genet Couns, 2013 Apr;22:258-67;Khan RS et al. J Am Heart Assoc, 2022 01;11:e022854). This variant was also reported in a non-compaction cardiomyopathy cohort (van Waning JI et al. J Am Coll Cardiol, 2018 02;71:711-722). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

MYH7-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 14, 2023

The MYH7 c.2678C>T variant is predicted to result in the amino acid substitution p.Ala893Val. This variant was reported in multiple individuals with dilated or noncompaction cardiomyopathy and was reported to segregate with disease in some families, although detailed information was not provided (Lakdawala et al. 2012. PubMed ID: 22464770; Table S1B, Walsh et al. 2016. PubMed ID: 27532257; Table S4, Kelly et al. 2018. PubMed ID: 29300372; Table 2a, van Waning et al. 2018. PubMed ID: 29447731; Table S2, Khan et al. 2021. PubMed ID: 34935411). This variant has not been reported in a large population database, indicating this variant is rare. This variant is classified as uncertain by the ClinGen Cardiomyopathy Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/177763/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

CardioboostCm

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

0.41

MutationAssessor

Pathogenic

3.5

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.1

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.026

Polyphen

0.84

Vest4

0.81

MutPred

0.41

Gain of catalytic residue at E894 (P = 0.2695);

MVP

0.99

MPC

1.9

ClinPred

0.99

GERP RS

5.0

Varity_R

0.66

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.86

SpliceAI score (max)

0.93

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.93

Position offset: 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