chr14-23429266-C-A
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000257.4(MYH7):c.1220G>T(p.Gly407Val) 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. 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. G407C) 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 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.1220G>T | p.Gly407Val | missense_variant | 13/40 | ENST00000355349.4 | |
MYH7 | NM_001407004.1 | c.1220G>T | p.Gly407Val | missense_variant | 12/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.1220G>T | p.Gly407Val | missense_variant | 13/40 | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 06, 2018 | The p.Gly407Val variant in MYH7 has been identified in 2 individuals with HCM (V an Driest 2004, LMM data) and was absent from large population studies. This var iant has also been reported in ClinVar (Variation ID #42831). Computational pred iction tools and conservation analysis suggest that the p.Gly407Val variant may impact the protein, though this information is not predictive enough to determin e pathogenicity. Of note, this variant lies in the head region of the protein. M issense variants in this region have been reported and statistically indicated t o be more likely to cause disease (Walsh 2016). In summary, although additional studies are required to fully establish its clinical significance, the p.Gly407V al variant is likely pathogenic. ACMG/AMP Criteria applied: PM1; PM2; PP3; PS4_S upporting. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 21, 2022 | ClinVar contains an entry for this variant (Variation ID: 42831). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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). 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"). This missense change has been observed in individual(s) with ‚Äãhypertrophic cardiomyopathy (PMID: 15358028, 27532257). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 407 of the MYH7 protein (p.Gly407Val). - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 08, 2020 | The p.G407V variant (also known as c.1220G>T), located in coding exon 11 of the MYH7 gene, results from a G to T substitution at nucleotide position 1220. The glycine at codon 407 is replaced by valine, an amino acid with dissimilar properties, and is located in the head domain. This variant has been detected in hypertrophic cardiomyopathy (HCM) cohorts; however, detail was limited (Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Aug;44:602-10; Walsh R et al. Genet. Med., 2017 02;19:192-203). Based on internal structural analysis, this variant is anticipated to be structurally disruptive (Planelles-Herrero VJ. Nat Commun. 2017 08;8(1):190). A likely pathogenic variant affecting the same codon (p.G407C, c.1219G>T) has been reported in association with HCM (Guo Q et al. DNA Cell Biol., 2014 Oct;33:699-704). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at