rs397515894
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000256.3(MYBPC3):c.1235_1236del(p.Phe412Ter) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
MYBPC3
NM_000256.3 frameshift
NM_000256.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.83
Genes affected
MYBPC3 (HGNC:7551): (myosin binding protein C3) MYBPC3 encodes the cardiac isoform of myosin-binding protein C. Myosin-binding protein C is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. MYBPC3 is expressed exclusively in heart muscle and is a key regulator of cardiac contraction. Mutations in this gene are a frequent cause of familial hypertrophic cardiomyopathy. [provided by RefSeq, May 2022]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-47343135-CAA-C is Pathogenic according to our data. Variant chr11-47343135-CAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 42514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47343135-CAA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.1235_1236del | p.Phe412Ter | frameshift_variant | 15/35 | ENST00000545968.6 | NP_000247.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.1235_1236del | p.Phe412Ter | frameshift_variant | 15/35 | 5 | NM_000256.3 | ENSP00000442795 | P4 | |
MYBPC3 | ENST00000399249.6 | c.1235_1236del | p.Phe412Ter | frameshift_variant | 14/34 | 5 | ENSP00000382193 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.1235_1236del | p.Phe412Ter | frameshift_variant, NMD_transcript_variant | 15/27 | 5 | ENSP00000444259 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Dec 31, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 19, 2023 | PM2, PS4_moderate, PVS1 - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 08, 2023 | Identified in multiple patients with HCM referred to GeneDx and in published literature (Richard et al., 2003; Van Driest et al., 2004; Ehlermann et al., 2008; Berge et al., 2014; Kapplinger et al., 2014; Viswanathan et al., 2017); of note, this variant is also described as del TT[10512-10513] and I411 fs/0; 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; Not observed in large population cohorts (gnomAD); Reported in ClinVar as pathogenic (ClinVar Variant ID# 42514; ClinVar); This variant is associated with the following publications: (PMID: 24111713, 24510615, 12707239, 18957093, 15519027, 29121657, 35653365) - |
Hypertrophic cardiomyopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 13, 2023 | This sequence change creates a premature translational stop signal (p.Phe412*) 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: 12707239, 18957093, 24111713, 24510615). ClinVar contains an entry for this variant (Variation ID: 42514). 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 09, 2019 | The p.Phe412X variant in MYBPC3 has been reported in >3 individuals with HCM (Richard 2003, Van Driest 2004, LMM data) and was absent from large population studies. It has also been reported in ClinVar (Variant ID: 42514). This variant is a deletion of 2 bases resulting in a premature termination codon at position 412, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in individuals with HCM. In summary, the p.Phe412X variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PVS1, PM2, PS4_Supporting. - |
Cardiovascular phenotype Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 04, 2016 | Variant summary: The MYBPC3 c.1235_1236delTT (p.Phe412Terfs) variant is a frameshift mutation predicted to cause loss of normal protein function due to production of a truncated protein or by the absence of the protein product due to nonsense-mediated mRNA decay. Mutation taster predicts a damaging outcome for this variant. It was not found in 102952 control chromosomes while it was reported in several patients with HCM from the literature. In one family, the variant co-segregated with disease, indicating pathogenicity. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Leu667fs), further supporting a deleterious outcome. In addition, clinical diagnostic laboratories and reputable databases classified this variant as Pathogenic. Taken together, this variant was classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 23, 2023 | The c.1235_1236delTT pathogenic mutation, located in coding exon 15 of the MYBPC3 gene, results from a deletion of two nucleotides at nucleotide positions 1235 to 1236, causing a translational frameshift with a predicted alternate stop codon (p.F412*). This alteration, also referred to as del TT[10512-10513] or I411 fs/0, has been reported in individuals with hypertrophic cardiomyopathy (Richard P et al. Circulation, 2003 May;107:2227-32; Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Nov;44:1903-10). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. - |
Cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 13, 2020 | This variant deletes 2 nucleotides in exon 15 of the MYBPC3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals and in a family affected with hypertrophic cardiomyopathy or referred for hypertrophic cardiomyopathy genetic testing (PMID: 12707239, 18957093, 24111713, 24510615). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at