rs397516212
Variant summary
Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PS1PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_000257.4(MYH7):c.438G>T(p.Lys146Asn) variant causes a missense change involving the alteration of a non-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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Synonymous variant affecting the same amino acid position (i.e. K146K) has been classified as Likely benign.
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 21 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.438G>T | p.Lys146Asn | missense_variant | 5/40 | ENST00000355349.4 | |
MYH7 | NM_001407004.1 | c.438G>T | p.Lys146Asn | missense_variant | 4/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.438G>T | p.Lys146Asn | missense_variant | 5/40 | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 13, 2019 | 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: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. This variant has been reported in several individuals with hypertrophic cardiomyopathy (HCM) and observed to be de novo in an individual affected with HCM (PMID: 28615295, 18403758, 27532257). ClinVar contains an entry for this variant (Variation ID: 43013). This sequence change replaces lysine with asparagine at codon 146 of the MYH7 protein (p.Lys146Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is not present in population databases (ExAC no frequency). - |
Pathogenic, no assertion criteria provided | research | Agnes Ginges Centre for Molecular Cardiology, Centenary Institute | Feb 26, 2020 | This MYH7 Lys146Asn variant has been reported as a de novo mutation in a sporadic childhood cardiomyopathy case (Morita H, et al., 2008). This mutation is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Here we report this variant in 3 unrelated HCM index cases (Ingles, et al., 2005; Ingles et al., 2017). In one of our families this variant segregates to multiple affected individuals (5 meiosis). In silico tools PolyPhen2, SIFT and MutationTaster predict this variant to be deleterious. Furthermore functional studies suggest that this variant disrupts the interaction of the N-terminus and lever arm of the myosin heavy chain protein and the drosophila model recapitulated a cardiomyopathy phenotype (Trujillo et al., 2017). Based on the adapted ACMG criteria (Kelly MA, et al., 2018) this variant has been shown to have a damaging affect on protein in a functional study (PS3), is rare in the general population (PM2), as been reported in a de novo case (PM6), segregates with disease (PP1_moderate), has been reported in HCM probands (PS4_supporting) and multiple in silico tools predict that this variant is deleterious (PP3), therefore we classify MYH7 Lys146Asn as 'Pathogenic'. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 21, 2013 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 31, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at