rs727503252
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_000257.4(MYH7):c.2782G>A(p.Asp928Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D928V) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
MYH7
NM_000257.4 missense
NM_000257.4 missense
Scores
12
5
3
Clinical Significance
Conservation
PhyloP100: 7.74
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 chr14-23424046-T-A is described in Lovd as [Likely_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, 0.934
PP5
Variant 14-23424047-C-T is Pathogenic according to our data. Variant chr14-23424047-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 164313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23424047-C-T is described in Lovd as [Pathogenic]. Variant chr14-23424047-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461894Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 727248
GnomAD4 exome
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1
AN:
1461894
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34
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0
AN XY:
727248
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
Bravo
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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
| Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 21, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 11, 2024 | Reported in multiple unrelated individuals with HCM in the published literature (PMID: 12974739, 15856146, 20038417, 27532257, 28193612, 28687478, 29121657); Not observed at significant frequency 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: 23982742, 15856146, 12974739, 27532257, 28193612, 28606303, 28687478, 29121657, 30972196, 37194601, 37609317, 34694434, 36136372, 34542152, 20038417, 29300372) - |
Hypertrophic cardiomyopathy Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 24, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). 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. ClinVar contains an entry for this variant (Variation ID: 164313). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12974739, 15856146, 20038417, 27532257, 28193612). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 928 of the MYH7 protein (p.Asp928Asn). - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 26, 2014 | The Asp928Asn variant in MYH7 has been reported in 3 individuals with HCM and se gregated with disease in at least 2 affected relatives from 2 families (Erdmann 2003, Perrot 2005, Gimeno 2009). In addition, this variant has also been identif ied by our laboratory in 2 individuals with HCM and segregated with disease in 2 affected relatives. It has not been identified in large population studies. Com putational prediction tools and conservation analysis do not provide strong supp ort for or against an impact to the protein. In summary, although additional stu dies are required to fully establish its clinical significance, its absence in c ontrol populations and segregation with disease support that this variant is lik ely pathogenic. - |
Cardiovascular phenotype Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 24, 2019 | The p.D928N variant (also known as c.2782G>A), located in coding exon 21 of the MYH7 gene, results from a G to A substitution at nucleotide position 2782. The aspartic acid at codon 928 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (HCM) and showed some limited segregation with disease (Erdmann J et al. Clin Genet. 2003 Oct;64(4):339-49; Perrot AJ Mol. Med. 2005 Jun;83(6):468-77; Gimeno JR Rev Esp Cardiol. 2009 Dec;62(12):1473-7; García-Molina E et al. Am J Transl Res. 2019 Mar;11(3):1724-1735). Other alterations affecting this amino acid (p.D928A, p.D928G, and p.D928V) have been reported in individuals with HCM (Michels M. Eur. Heart J. 2009 Nov;30(21):2593-8; 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, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MutPred
Gain of catalytic residue at M932 (P = 2e-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