rs727503266
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5
The NM_000257.4(MYH7):c.1283C>T(p.Ala428Val) 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. A428D) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.1283C>T | p.Ala428Val | missense_variant | 14/40 | ENST00000355349.4 | |
MYH7 | NM_001407004.1 | c.1283C>T | p.Ala428Val | missense_variant | 13/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.1283C>T | p.Ala428Val | missense_variant | 14/40 | 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:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 05, 2022 | 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. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 428 of the MYH7 protein (p.Ala428Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic and/or dilated cardiomyopathy (PMID: 12707239, 27532257, 32894683). ClinVar contains an entry for this variant (Variation ID: 164375). 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 C0"). 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). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 28, 2018 | The p.Ala428Val variant in MYH7 has been identified in 4 individuals with hypert rophic cardiomyopathy (HCM; Richard 2003, Van Driest 2004, Walsh 2017, LMM data) and is absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This varia nt is located in the head domain of the MYH7 protein, where studies have shown t hat variants in this region have an increased probability for causing disease (W alsh 2017). In summary, although additional studies are required to fully establ ish its clinical significance, this variant meets criteria to be classified as l ikely pathogenic for autosomal dominant HCM based upon its presence in multiple affected individuals, absence from the general population, presence in a functio nal domain and computational evidence. ACMG/AMP Criteria applied: PS4_Supporting , PM1, PM2, PP3. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 10, 2023 | Reported in association with HCM in published literature (Richard et al., 2003; Van Driest et al., 2004; Walsh et al., 2017; Mattivi et al., 2020); 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: 15358028, 12707239, 32894683, 27532257, 29300372) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at