14-23425357-C-G
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP2PP3PP5_Very_Strong
The NM_000257.4(MYH7):c.2348G>C(p.Arg783Pro) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R783H) has been classified as Pathogenic.
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Primary dilated cardiomyopathy Pathogenic:1
The p.Arg783Pro variant in MYH7 has been reported as an apparently de novo occur rence in 1 individual with DCM and skeletal myopathy (Homayoun 2011). This varia nt was absent from large population studies, but has been reported in ClinVar (V ariation ID: 42895). Of note, this variant lies in the head region of the protei n. Missense variants in this region have been reported and statistically indicat ed to be more likely to cause disease (Walsh 2016). In summary, although additio nal studies are required to fully establish its clinical significance, the p.Arg 783Pro variant is likely pathogenic. -
Hypertrophic cardiomyopathy Pathogenic:1
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: "Possibly Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 42895). This missense change has been observed in individual(s) with dilated or hypertrophic cardiomyopathy as well as in individuals with congenital myopathy (PMID: 21211974, 22464770, 24503780, 27532257, 33673806). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 783 of the MYH7 protein (p.Arg783Pro). -
Primary familial hypertrophic cardiomyopathy Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at