rs121913634

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000257.4(MYH7):c.2333A>T(p.Asp778Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D778N) has been classified as Likely pathogenic.

Frequency

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

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.61

Publications

12 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 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 chr14-23425373-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 181369.

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, 0.984

PP5

Variant 14-23425372-T-A is Pathogenic according to our data. Variant chr14-23425372-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 454354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4 link	c.2333A>T	p.Asp778Val	missense_variant	Exon 21 of 40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1 link	c.2333A>T	p.Asp778Val	missense_variant	Exon 20 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MYH7	ENST00000355349.4 link	c.2333A>T	p.Asp778Val	missense_variant	Exon 21 of 40	1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000713768.1 link	c.2333A>T	p.Asp778Val	missense_variant	Exon 21 of 41			ENSP00000519070.1
MYH7	ENST00000713769.1 link	c.2333A>T	p.Asp778Val	missense_variant	Exon 20 of 39			ENSP00000519071.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152124

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

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41404

American (AMR)

AF:

0.00

AC:

AN:

15278

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:

4820

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:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2094

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:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy

Pathogenic:2

Jan 08, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 15358028, 21674835). ClinVar contains an entry for this variant (Variation ID: 454354). This sequence change replaces aspartic acid with valine at codon 778 of the MYH7 protein (p.Asp778Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (ExAC no frequency). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Asp778 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11748309, 12707239, 22112859, 27247418). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Dec 11, 2019

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

MYH7 Asp778Val has been identified previously in 2 HCM probands (Capek P, et al., 2011; Van Driest SL, et al., 2004). The variant is present at a low frequency in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We have identified this variant in a single HCM proband who presented with asymmetric hypertrophy (Ingles et al 2017). This proband also carries a second MYH7 variant (Arg1818Val) in trans with this MYH7 Asp778Val. A deceased family member was diagnosed with HCM at post-mortem and only MYH7 Asp778Val was found to segregate to the decedent. Computational tools SIFT, PolyPhen-2, PolyPhen-HCM and MutationTaster predict this variant to have a deleterious effect. Interestingly another variant at this position (c.2334C>G Asp778Glu) has been classified as pathogenic, suggesting that an amino acid substitution at this site may not be tolerated. In a large HCM population study Walsh et al., showed that MYH7 variants identified in HCM cases were found to cluster between amino acids 181- 937 (2017), this implies that variants in this region are likely to cause a HCM phenotype. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant is located in a known functional domain of MYH7 (PM1), is rare in the general population (PM2), and another variant at this position has been classified as pathogenic (PM5). It has also has been identified in more than 2 HCM probands (PS4_supporting) and in silico tools predict the variant to be deleterious (PP3), therefore we classify MYH7 Asp778Val as "likely pathogenic". -

Hypertrophic cardiomyopathy 1

Pathogenic:1

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, however, missense variants have been proposed to act in a dominant negative manner (PMID: 24714796). (I) 0108 - This gene is associated with both recessive and dominant disease. Pathogenic variants in this gene are usually heterozygous, however a recessive inheritance pattern has been observed in severe cases (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 29300372). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to valine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional myosin head domain (PMID: 29300372). (SP) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. These alternative changes (p.Asp778Gly, p.Asp778Glu, p.Asp778His, p.Asp778Asn) have been reported as likely pathogenic and pathogenic, and observed in multiple patients with hypertrophic cardiomyopathy (HCM) and ventricular hypertrophy (LOVD, ClinVar, PMID: 27885498, PMID: 30165862). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been repeatedly classified as either likely pathogenic or pathogenic, and reported in multiple patients with HCM (LOVD, ClinVar, PMID: 15358028, PMID: 21674835, PMID: 22455086, PMID: 28408708, PMID: 30847666). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.64

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.6

PhyloP100

7.6

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-7.5

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0080

Polyphen

0.98

Vest4

0.98

MutPred

0.79

Gain of MoRF binding (P = 0.0247);

MVP

0.99

MPC

2.5

ClinPred

1.0

GERP RS

4.6

Varity_R

0.68

gMVP

0.99

Mutation Taster

=0/100

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over