rs121913627
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1PM1PM2PM5PP2PP3
The NM_000257.4(MYH7):c.1816G>T(p.Val606Leu) 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 Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V606M) 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 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Uncertain:1
This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 606 of the MYH7 protein (p.Val606Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant has not been reported in the literature in individuals with MYH7-related disease. It has, however, been reported in an unaffected individual (PMID: 24704860). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). A different missense substitution at this codon (p.Val606Met) has been determined to be pathogenic (PMID: 27532257, 1552912, 9172070, 18020371). This suggests that the valine residue is critical for MYH7 protein function and that other missense substitutions at this position may also be pathogenic. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at