rs397516272
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_Strong
The NM_000257.4(MYH7):c.872C>T(p.Ser291Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,510 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S291P) 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 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.872C>T | p.Ser291Phe | missense_variant | 10/40 | ENST00000355349.4 | |
MYH7 | NM_001407004.1 | c.872C>T | p.Ser291Phe | missense_variant | 9/39 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.872C>T | p.Ser291Phe | missense_variant | 10/40 | 1 | NM_000257.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461510Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727108
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Genetics and Molecular Cardiology, University of São Paulo | - | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 10, 2018 | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ser291Phe variant in MYH7 has been identified by our laboratory in 2 individuals with HCM . One of these individuals had a second disease-causing variant in MYH7 and pres ented at an earlier age. This variant was absent from large population studies. Computational prediction tools and conservation analysis suggest that the p.Ser2 91Phe variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additionally, this variant lies in the head r egion of the protein. Missense variants in this region have been reported and st atistically indicated to be more likely to cause disease (Walsh 2016). In summar y, while there is some suspicion for a pathogenic role, the clinical significanc e of the p.Ser291Phe variant is uncertain. ACMG/AMP Criteria applied: PM1; PM2; PP3. - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 17, 2020 | This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with phenylalanine at codon 291 of the MYH7 protein (p.Ser291Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 21943931, 27247418, 24093860). ClinVar contains an entry for this variant (Variation ID: 43110). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 04, 2021 | The p.S291F variant (also known as c.872C>T), located in coding exon 8 of the MYH7 gene, results from a C to T substitution at nucleotide position 872. The serine at codon 291 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This variant has been reported in hypertrophic cardiomyopathy (HCM) clinical and genetic testing cohorts; however, limited details were provided (Lakdawala NK et al. Am J Cardiol, 2011 Dec;108:1606-13; Marsiglia JD et al. Am Heart J, 2013 Oct;166:775-82; Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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