rs868789318
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3PP5
The NM_000257.4(MYH7):c.2581G>A(p.Glu861Lys) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E861G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.2581G>A | p.Glu861Lys | missense_variant | 22/40 | ENST00000355349.4 | |
MYH7 | NM_001407004.1 | c.2581G>A | p.Glu861Lys | missense_variant | 21/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.2581G>A | p.Glu861Lys | missense_variant | 22/40 | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Ventricular tachycardia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Agnes Ginges Centre for Molecular Cardiology, Centenary Institute | Dec 02, 2017 | The MYH7 Glu861Lys variant has been previously identified in a DCM proband (Invitae, Pers. Comm.), and is absent from the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) and the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We identified this variant in a proband who presented with a resuscitated cardiac arrest, the patient has no clinical manifestations of any cardiomyopathy, however upon screening 3 family members were diagnosed with DCM and all 3 were found to also harbour the Glu861Lys variant. In a large HCM population study Walsh et al., identified that MYH7 variants identified in cases were found to cluster between amino acids 181- 937 (2017), this implies that variants in this region are likely to cause cardiomyopathy. Computational tools MutationTaster, SIFT, PolyPhen-2 and PolyPhen-HCM predict this variant to be deleterious. In summary, the variant is extremely rare in the general population, segregates with affected individuals, is located in a well known "hotspot" of MYH7 and in silico tools predict the variant to be disease-causing, therefore we classify MYH7 Glu861Lys as "likely pathogenic". - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 18, 2022 | This variant has not been reported in the literature in individuals affected with MYH7-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 237434). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 861 of the MYH7 protein (p.Glu861Lys). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at