rs727504558
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_000257.4(MYH7):c.2783A>T(p.Asp928Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. D928N) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
MYH7
NM_000257.4 missense
NM_000257.4 missense
Scores
14
5
1
Clinical Significance
Conservation
PhyloP100: 7.85
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PM1
In a helix (size 120) in uniprot entity MYH7_HUMAN there are 91 pathogenic changes around while only 3 benign (97%) 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 chr14-23424047-C-T is described in Lovd as [Pathogenic].
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH7. . Gene score misZ: 3.9329 (greater than the threshold 3.09). Trascript score misZ: 6.7889 (greater than threshold 3.09). The gene has 341 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. GenCC has associacion of the gene with hyaline body myopathy, MYH7-related skeletal myopathy, dilated cardiomyopathy 1S, congenital myopathy 7A, myosin storage, autosomal dominant, dilated cardiomyopathy, left ventricular noncompaction, myopathy, myosin storage, autosomal dominant, hypertrophic cardiomyopathy, congenital heart disease, Ebstein anomaly, arrhythmogenic right ventricular cardiomyopathy, myopathy, myosin storage, autosomal recessive, hypertrophic cardiomyopathy 1, familial isolated dilated cardiomyopathy.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.932
PP5
Variant 14-23424046-T-A is Pathogenic according to our data. Variant chr14-23424046-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 181379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23424046-T-A is described in Lovd as [Likely_pathogenic]. Variant chr14-23424046-T-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:5Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 02, 2019 | Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27247418, 19666645, 31323898) - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Hypertrophic cardiomyopathy Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 29, 2022 | ClinVar contains an entry for this variant (Variation ID: 181379). 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. This variant disrupts the p.Asp928 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12974739, 15856146, 20038417, 27532257). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 19666645, 27247418, 31323898). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 928 of the MYH7 protein (p.Asp928Val). - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, flagged submission | clinical testing | Ambry Genetics | Sep 06, 2017 | The p.D928V variant (also known as c.2783A>T), located in coding exon 21 of the MYH7 gene, results from an A to T substitution at nucleotide position 2783. The aspartic acid at codon 928 is replaced by valine, an amino acid with highly dissimilar properties. This alteration has been reported in individuals with hypertrophic cardiomyopathy (HCM) (Michels M. Eur. Heart J. 2009 Nov;30(21):2593-8). Other alterations affecting this amino acid (p.D928A, p.D928G, and p.D928N) have been reported in individuals with HCM (Erdmann J et al. Clin Genet. 2003 Oct;64(4):339-49; Lopes LR et al. Heart, 2015 Feb;101:294-301; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
CardioboostCm
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MutPred
Gain of catalytic residue at M932 (P = 5e-04);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at