rs397516218

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP2PP3_ModeratePP5

The NM_000257.4(MYH7):c.4487A>C(p.Glu1496Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1496K) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:5

Conservation

PhyloP100: 7.76

Publications

1 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 links:

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]

MHRT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 20 uncertain in NM_000257.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-23417186-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2155573.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the MYH7 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 341 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 3.9329 (above the threshold of 3.09). Trascript score misZ: 6.7889 (above the threshold of 3.09). GenCC associations: The gene is linked to myopathy, myosin storage, autosomal recessive, MYH7-related skeletal myopathy, congenital myopathy 7A, myosin storage, autosomal dominant, Ebstein anomaly, hyaline body myopathy, left ventricular noncompaction, hypertrophic cardiomyopathy 1, dilated cardiomyopathy 1S, dilated cardiomyopathy, congenital heart disease, familial isolated dilated cardiomyopathy, myopathy, myosin storage, autosomal dominant, arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.931

PP5

Variant 14-23417185-T-G is Pathogenic according to our data. Variant chr14-23417185-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43021.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4 link	c.4487A>C	p.Glu1496Ala	missense_variant	Exon 32 of 40	ENST00000355349.4	NP_000248.2	P12883
MYH7	NM_001407004.1 link	c.4487A>C	p.Glu1496Ala	missense_variant	Exon 31 of 39		NP_001393933.1
MHRT	NR_126491.1 link	n.652-27T>G		intron_variant	Intron 4 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYH7	ENST00000355349.4 link	c.4487A>C	p.Glu1496Ala	missense_variant	Exon 32 of 40	1	NM_000257.4	ENSP00000347507.3	P12883
MYH7	ENST00000713768.1 link	c.4487A>C	p.Glu1496Ala	missense_variant	Exon 32 of 41			ENSP00000519070.1
MYH7	ENST00000713769.1 link	c.4487A>C	p.Glu1496Ala	missense_variant	Exon 31 of 39			ENSP00000519071.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152142

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:

0.0000159

AC:

AN:

251492

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

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:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41442

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000413

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Sep 06, 2017

Blueprint Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYH7: PM2, PS4:Moderate -

Sep 30, 2015

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Glu1496Ala (GAG>GCG): c.4487 A>C in exon 32 of the MYH7 gene (NM_000257.2). The E1496A mutation in the MYH7 gene has been previously reported in one individual with HCM and the mutation was absent from 168 control individuals (Zeller R et al., 2006). Furthermore, the E1496A mutation was not observed inapproximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E1496A variant is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. Mutations in nearby residues (Y1488C, S1491C, R1500W) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. In summary, E1496A in the MYH7 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s). -

Hypertrophic cardiomyopathy

Pathogenic:1

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 1496 of the MYH7 protein (p.Glu1496Ala). This variant is present in population databases (rs397516218, gnomAD 0.002%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 16715312, 24793961; internal data). ClinVar contains an entry for this variant (Variation ID: 43021). 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%. For these reasons, this variant has been classified as Pathogenic. -

not specified

Uncertain:1

Nov 20, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Cardiomyopathy

Uncertain:1

Mar 24, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces glutamic acid with alanine at codon 1496 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 at least five individuals affected with hypertrophic cardiomyopathy (PMID: 16715312, 24793961, 32894683, 33673806; ClinVar SCV001380773.4; Bonaventura 2021, dissertation, Charles University). This variant has been identified in 5/282872 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -

Myosin storage myopathy

Uncertain:1

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Cardiovascular phenotype

Uncertain:1

Jun 01, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.E1496A variant (also known as c.4487A>C), located in coding exon 30 of the MYH7 gene, results from an A to C substitution at nucleotide position 4487. The glutamic acid at codon 1496 is replaced by alanine, an amino acid with dissimilar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Zeller R et al. J Mol Med (Berl), 2006 Aug;84:682-91; Bos JM et al. Mayo Clin Proc, 2014 Jun;89:727-37; Hathaway J et al. BMC Cardiovasc Disord, 2021 03;21:126). This amino acid position is highly 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

CardioboostCm

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

0.51

MutationAssessor

Pathogenic

3.5

PhyloP100

7.8

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-4.6

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.027

Polyphen

0.92

Vest4

0.82

MutPred

0.64

Gain of methylation at K1499 (P = 0.1703);

MVP

0.90

MPC

1.6

ClinPred

0.99

GERP RS

5.3

Varity_R

0.72

gMVP

0.82

Mutation Taster

=6/94

disease causing (ClinVar)

(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