Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate
The NM_000257.4(MYH7):c.2480G>C(p.Trp827Ser) 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. 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. W827C) has been classified as Uncertain significance.
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
Our verdict: Pathogenic. The variant received 11 ACMG points.
PM1
In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_000257.4
PM2
Very rare variant in population databases, with high coverage;
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, 0.947
PP5
Variant 14-23424968-C-G is Pathogenic according to our data. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23424968-C-G is described in CliVar as Likely_pathogenic. Clinvar id is 1184902.Status of the report is criteria_provided_single_submitter, 1 stars.