rs397516154
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PM1PM2PM5PP2PP5BP4
The NM_000257.4(MYH7):āc.2525G>Cā(p.Ser842Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. S842N) has been classified as Pathogenic.
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYH7 | NM_000257.4 | c.2525G>C | p.Ser842Thr | missense_variant | 22/40 | ENST00000355349.4 | NP_000248.2 | |
MYH7 | NM_001407004.1 | c.2525G>C | p.Ser842Thr | missense_variant | 21/39 | NP_001393933.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYH7 | ENST00000355349.4 | c.2525G>C | p.Ser842Thr | missense_variant | 22/40 | 1 | NM_000257.4 | ENSP00000347507.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461890Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727244
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 19, 2023 | This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 842 of the MYH7 protein (p.Ser842Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant MYH7 associated conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 629474). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function. This variant disrupts the p.Ser842 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30384889). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 09, 2018 | Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the myosin head/motor domain (S1 domain) of the MYH7 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at