rs727503211
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000256.3(MYBPC3):c.966G>A(p.Trp322Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,476 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 Pathogenic (★★). 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.966G>A | p.Trp322Ter | stop_gained | 12/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.966G>A | p.Trp322Ter | stop_gained | 12/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.966G>A | p.Trp322Ter | stop_gained | 11/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.966G>A | p.Trp322Ter | stop_gained, NMD_transcript_variant | 12/27 | 5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1457476Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 724662
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Dec 16, 2016 | p.Trp322X (c.966G>A) in exon 12 of the MYBPC3 gene (NM_000256.3) We have seen this variant in a person with HCM. Testing was performed by Invitae. Truncating variants are an established mechanism of disease for this gene. Therefore, we consider this variant to be very likely disease-causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). There is weak case data for this variant, which has been seen in at least 2 unrelated cases of HCM (not including this patient's family). The variant has not been reported in the literature. It is also listed on cardiodb.org as present in the cohort of OMGL/LMM HCM cohort, classified as pathogenic. There is no variation at codon 322 listed in the Exome Aggregation Consortium dataset (ExAC; http://exac.broadinstitute.org/), which includes variant calls on ~64,000 unrelated individuals of African, Asian, European, and Latino descent or the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in ExAC is mean 24x, median 19x, and >90% of people have 10x coverage. The average coverage at that site in gnomAD is median ~25x, mean ~30x, and >90% of people have 10x coverage. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 17, 2019 | Not observed in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported in ClinVar as pathogenic (ClinVar Variant ID# 164136; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27532257, 25611685) - |
Hypertrophic cardiomyopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change creates a premature translational stop signal (p.Trp322*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 25611685; Invitae). ClinVar contains an entry for this variant (Variation ID: 164136). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 14, 2015 | The p.Trp322X variant in MYBPC3 has been reported by our laboratory in two indiv iduals with HCM (childhood-onset in one of them). It has not been identified in large population studies. This nonsense variant leads to a premature termination codon at position 322, which is predicted to lead to a truncated or absent prot ein. Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in individuals with HCM. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon the predicted impact of the variant. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 19, 2018 | The p.W322* pathogenic mutation (also known as c.966G>A), located in coding exon 12 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 966. This changes the amino acid from a tryptophan to a stop codon within coding exon 12. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Alfares AA et al. Genet. Med., 2015 Nov;17:880-8). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at