chr11-47337452-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000256.3(MYBPC3):c.2541C>A(p.Tyr847Ter) variant causes a stop gained 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y847Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000256.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.2541C>A | p.Tyr847Ter | stop_gained | 25/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.2541C>A | p.Tyr847Ter | stop_gained | 25/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.2541C>A | p.Tyr847Ter | stop_gained | 24/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.*46C>A | 3_prime_UTR_variant, NMD_transcript_variant | 25/27 | 5 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 25, 2021 | The p.Tyr847X variant in MYBPC3 has been reported in 1 individual with hypertrophic cardiomyopathy (Alfares 2015 PMID: 25611685; Walsh 2017 PMID: 27532257; LMM data). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 847, which is predicted to lead to a truncated or absent protein. Loss of function of the MYBPC3 gene is an established disease mechanism in autosomal dominant HCM. Another variant involving this codon (c.2541C>G, p.Tyr847X) has been identified in individuals with hypertrophic cardiomyopathy and is classified as pathogenic by this and other laboratories. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hypertrophic cardiomyopathy. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM5. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 11, 2020 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This nonsense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 15519027, 25611685, 29121657). ClinVar contains an entry for this variant (Variation ID: 177852). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr847*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at