14-23417657-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate
The NM_000257.4(MYH7):c.4199C>G(p.Ala1400Gly) 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1400D) 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.4199C>G | p.Ala1400Gly | missense_variant | 31/40 | ENST00000355349.4 | |
MYH7 | NM_001407004.1 | c.4199C>G | p.Ala1400Gly | missense_variant | 30/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.4199C>G | p.Ala1400Gly | missense_variant | 31/40 | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 34
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 10, 2019 | Not observed [at a significant frequency] in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29121657) - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 02, 2021 | This sequence change replaces alanine with glycine at codon 1400 of the MYH7 protein (p.Ala1400Gly). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and glycine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 29121657). ClinVar contains an entry for this variant (Variation ID: 181248). 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"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 19, 2020 | The p.A1400G variant (also known as c.4199C>G), located in coding exon 29 of the MYH7 gene, results from a C to G substitution at nucleotide position 4199. The alanine at codon 1400 is replaced by glycine, an amino acid with similar properties. This variant has been detected in a hypertrophic cardiomyopathy cohort; however, details were limited (Viswanathan SK et al. PLoS ONE, 2017 Nov;12:e0187948). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at