rs727503276
Variant summary
Our verdict is Pathogenic. Variant got 27 ACMG points: 27P and 0B. PS1_Very_StrongPM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000257.4(MYH7):c.739T>C(p.Phe247Leu) 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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F247C) 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 27 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.739T>C | p.Phe247Leu | missense_variant | 9/40 | ENST00000355349.4 | |
MYH7 | NM_001407004.1 | c.739T>C | p.Phe247Leu | missense_variant | 8/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.739T>C | p.Phe247Leu | missense_variant | 9/40 | 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:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 02, 2016 | The p.Phe247Leu variant in MYH7 has been reported in 5 individuals with HCM and segregated with disease in 5 affected relatives from 2 families, including 2 aff ected obligate carriers (Garcia-Castro 2009, Coto 2012, LMM data). This variant was absent from large population studies. Phenylalanine (Phe) at position 247 is highly conserved in mammals and across evolutionarily distant species and the c hange to leucine (Leu) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is es timated to be correct 94% of the time (Jordan 2011). In summary, although additi onal studies are required to fully establish its clinical significance, the p.Ph e247Leu variant is likely pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 18, 2022 | The p.F247L variant (also known as c.739T>C), located in coding exon 7 of the MYH7 gene, results from a T to C substitution at nucleotide position 739. The phenylalanine at codon 247 is replaced by leucine, an amino acid with highly similar properties. This variant was detected in an individual with hypertrophic cardiomyopathy (HCM) and his affected relative, as well as reported in individuals from HCM cohorts with limited clinical information provided (García-Castro M et al. Rev Esp Cardiol, 2009 Jan;62:48-56; Coto E et al. J Mol Diagn, 2012 Sep;14:518-24; Walsh R et al. Genet. Med., 2017 02;19:192-203). Additional segregation with disease has been reported in a family with HCM who had testing performed at outside laboratories (personal communication). In addition, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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