rs397516268
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5
The NM_000257.4(MYH7):c.748A>T(p.Ile250Phe) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I250V) has been classified as Uncertain significance.
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.748A>T | p.Ile250Phe | missense_variant | 9/40 | ENST00000355349.4 | |
MYH7 | NM_001407004.1 | c.748A>T | p.Ile250Phe | missense_variant | 8/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.748A>T | p.Ile250Phe | 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
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 29, 2012 | p.Ile250Phe (ATT>TTT): c.748 A>T in exon 9 of the MYH7 gene. The Ile250Phe variant in the MYH7 gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. Ile250Phe results in a non-conservative amino acid substitution of a smaller hydrophobic Isoleucine with a larger hydrophobic Phenylalanine residue at a position that is highly conserved throughout evolution. Mutations in nearby codons (Phe247Leu, Arg249Gln, His251Asn) have been reported in association with HCM, further supporting the functional importance of this region of the protein. Furthermore, in silico analysis predicts Ile250Phe is probably damaging to the protein structure/function (Adzhubei et al., 2000; Schwarz et al., 2011). The NHLBI ESP Exome Variant Server reports Ile250Phe was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations (NHLBI ESP). Therefore, while Ile250Phe is a good candidate for a disease-causing mutation, we cannot unequivocally determine the clinical significance of this variant with the clinical and molecular information available at this time. The variant is found in HCM panel(s). - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2022 | This variant is not present in population databases (gnomAD no frequency). 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. 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 181323). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 250 of the MYH7 protein (p.Ile250Phe). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at