rs397515982
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000256.3(MYBPC3):c.2670G>A(p.Trp890*) variant causes a stop gained change involving the alteration of a 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 30)
Exomes 𝑓: 0.0000035 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
MYBPC3
NM_000256.3 stop_gained
NM_000256.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 7.55
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]
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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 11-47335944-C-T is Pathogenic according to our data. Variant chr11-47335944-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 42650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47335944-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYBPC3 | ENST00000545968.6 | c.2670G>A | p.Trp890* | stop_gained | 26/35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
| MYBPC3 | ENST00000399249.6 | c.2670G>A | p.Trp890* | stop_gained | 25/34 | 5 | ENSP00000382193.2 | |||
| MYBPC3 | ENST00000544791.1 | n.*175G>A | non_coding_transcript_exon_variant | 26/27 | 5 | ENSP00000444259.1 | ||||
| MYBPC3 | ENST00000544791 | n.*175G>A | 3_prime_UTR_variant | 25/26 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
30
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000353 AC: 5AN: 1414854Hom.: 0 Cov.: 34 AF XY: 0.00000143 AC XY: 1AN XY: 700004
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
5
AN:
1414854
Hom.:
Cov.:
34
AF XY:
AC XY:
1
AN XY:
700004
Gnomad4 AFR exome
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GnomAD4 genome
GnomAD4 genome
Cov.:
30
Bravo
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:13Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 30, 2021 | PVS1, PS4, PM2 - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | - | Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Trp890Stop (c.3670G>A). Based on the data reviewed below we consider it likely disease causing. In total the variant has been seen in at least 4 unrelated cases with weak segregation data. This variant was initially reported in one individual with HCM by Van Driest S et al (2004) then in two more affected members of one family reported by Ehlermann P et al (2008). The Seidman group report on their program website that they have seen this variant in their cohort (Merk, Seidman et al 2004). Brito et al (2012) observed the variant in one individual in their Portuguese HCM cohort. This is a nonsense variant predicted to cause loss of normal protein function either through premature protein truncation or nonsense-mediated mRNA decay. Many other truncating or null variants have been identified in MYBPC3 in association with cardiomyopathy (ex. p.Trp792fs, p.Pro794fs, p.Lys1065fs, p.Cys1202fs, p.Pro1208fs, p.Trp1098ter, p.Glu1096ter, p.Cys1124ter, p.Gln1233ter). Furthermore, these types of variants in MYBPC3 are not seen in individuals without cardiomyopathy (Pan et al 2012). In total the variant has not been seen in ~6700 published controls and publicly available general population sample. Van Driest et al (2004) report that p.Trp890Stop was not observed in 100 Caucasian and 100 African American presumably healthy individuals. Brito et al (2012) did not observe the variant in 100 control samples. GeneDx did not report internal control data. The variant is not listed in dbSNP or 1000 Genomes. In addition p.Trp890Stop is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6500 Caucasian and African American individuals (as of September 2012). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jul 07, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | May 11, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 05, 2022 | Identified in a patient with phenotypic features of both HCM and LVNC on cardiac imaging (Goncalves et al., 2022); Not observed in large population cohorts (gnomAD); Expression studies using patient heart tissue suggest that the p.(W890X) transcript is subject to nonsense-mediated mRNA decay (Helms et al., 2014); 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; This variant is associated with the following publications: (PMID: 15519027, 24510615, 25525159, 21415409, 18957093, 22857948, 27532257, 27688314, 25031304, 26265630, 33673806, 34542152, 22112859, 31447099, 35411935) - |
Hypertrophic cardiomyopathy Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change creates a premature translational stop signal (p.Trp890*) 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 individual(s) with hypertrophic cardiomyopathy (HCM) (PMID: 15114369, 15519027, 18533079, 18957093, 22857948). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42650). 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 | Nov 28, 2017 | The p.Trp890X variant in MYBPC3 has been reported in >10 individuals with HCM an d segregated with disease in at least 5 affected relatives (Van Driest 2004, Ehl ermann 2008, LMM data). It was absent from large population studies. This varian t has also been reported by other clinical laboratories in ClinVar (Variation ID 42650). This nonsense variant leads to a premature termination codon at positio n 890, which is predicted to lead to a truncated or absent protein. Heterozygous loss of MYBPC3 function is an established disease mechanism in HCM. In summary, the p.Trp890X variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based on upon segregation studies and the predicted impact to the protein. ACMG/AMP criteria applied: PVS1, PS4, PP1_Moderate. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Aug 25, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 19, 2023 | This variant changes 1 nucleotide in exon 26 of the MYBPC3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in more than ten unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 22857948, 24510615, 24793961, 27532257, 33673806, 33495596, 35411935, 35581268) and in two affected individuals in one family (PMID: 18957093). 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. - |
Left ventricular noncompaction 10 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 22, 2022 | - - |
Cardiomyopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 09, 2023 | This variant changes 1 nucleotide in exon 26 of the MYBPC3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in more than ten unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 15519027, 22857948, 24510615, 24793961, 27532257, 33673806, 33495596, 35411935, 35581268) and in two affected individuals in one family (PMID: 18957093). 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. - |
Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 12, 2021 | - - |
Hypertrophic cardiomyopathy 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 22, 2022 | - - |
Primary dilated cardiomyopathy;C1858725:Left ventricular noncompaction 1;C1861862:Hypertrophic cardiomyopathy 4 Other:1
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Pathogenic and reported on 02-25-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
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