rs397516042
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000256.3(MYBPC3):c.3811C>T(p.Arg1271*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000746 in 1,607,694 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000069 ( 0 hom. )
Consequence
MYBPC3
NM_000256.3 stop_gained
NM_000256.3 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 2.23
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 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 11-47332075-G-A is Pathogenic according to our data. Variant chr11-47332075-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47332075-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
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GnomAD3 genomes 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000813 AC: 2AN: 246124Hom.: 0 AF XY: 0.00000748 AC XY: 1AN XY: 133672
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cardiomyopathy Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 22, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 29, 2023 | This variant changes 1 nucleotide in exon 33 of the major myosin binding region of the MYBPC3 gene, creating a premature translation stop signal in the C-terminus region. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. A functional study using myomectomy samples from a carrier individual have shown reduced protein expression levels (PMID: 19574547). This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 18533079, 19574547, 23396983, 25524337, 27532257, 30297972, 31110529, 33495596; communication with external laboratories: ClinVar SCV000208206.13, SCV000059270.6). It has also been reported in one individual suspected to be affected with hypertrophic cardiomyopathy (PMID: 33673806), in one individual affected with cardiomyopathy (PMID: 28254189), and in homozygous state in one child affected with hypertrophic cardiomyopathy (DOI:10.32592/psj.21.3.194). A splicing variant occurring downstream of this variant is known to be disease-causing (ClinVar variation ID: 42746). This variant has been identified in 2/246124 chromosomes 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 17, 2022 | Variant summary: MYBPC3 c.3811C>T (p.Arg1271X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been associated with hypertrophic cardiomyopathy in HGMD and have been cited as pathogenic in ClinVar. The variant allele was found at a frequency of 8.1e-06 in 246124 control chromosomes (gnomAD). c.3811C>T has been reported in the literature in individuals affected with hypertrophic cardiomyopathy (examples: Martson_2009, Coppini_2014, Ho_2018, Hathaway_2021). These data indicate that the variant is likely to be associated with disease. Experimental evidence demonstrated absence of the expected truncated protein and significantly lower quantity of MyBP-C in myofibrils compared with non-failing donor heart muscle, as determined in myectomy sample(s) with the variant (Martson_2009). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=6) / likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Hypertrophic cardiomyopathy Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 08, 2024 | This variant changes 1 nucleotide in exon 33 of the major myosin binding region of the MYBPC3 gene, creating a premature translation stop signal in the C-terminus region. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. A functional study using myomectomy samples from a carrier individual have shown reduced protein expression levels (PMID: 19574547). This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 18533079, 19574547, 23396983, 25524337, 27532257, 30297972, 31110529, 33495596; communication with external laboratories: ClinVar SCV000208206.13, SCV000059270.6). It has also been reported in one individual suspected to be affected with hypertrophic cardiomyopathy (PMID: 33673806), in one individual affected with cardiomyopathy (PMID: 28254189), and in homozygous state in one child affected with hypertrophic cardiomyopathy (DOI:10.32592/psj.21.3.194). A splicing variant occurring downstream of this variant is known to be disease-causing (ClinVar variation ID: 42746). This variant has been identified in 2/246124 chromosomes 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 24, 2024 | This sequence change creates a premature translational stop signal (p.Arg1271*) in the MYBPC3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 4 amino acid(s) of the MYBPC3 protein. This variant is present in population databases (rs397516042, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18533079, 23396983, 33673806; Invitae). ClinVar contains an entry for this variant (Variation ID: 42744). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MYBPC3 function (PMID: 19574547). 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 | Jul 03, 2019 | The p.Arg1271X variant in MYBPC3 gene has been identified in 6 individuals with HCM and segregated with disease in 1 affected family member (Olivotto 2008, Marston 2009, Lopes 2013, Walsh 2017, LMM data). It was also identified in 1 individual with early onset DCM who carried an additional pathogenic variant in MYBCP3 (LMM data). It has been identified in 2/246124 chromosomes by gnomAD (https://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID #42744). This nonsense variant leads to a premature termination codon at position 1271, which is predicted to lead to a truncated or absent protein. Loss of function of the MYBCP3 gene is an established disease mechanism in autosomal dominant HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate. - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 26, 2024 | Identified in individuals with HCM referred for genetic testing at GeneDx and in published literature (PMID: 18533079, 23396983, 28254189, 27532257, 30297972, 31110529); Reported in one patient with early onset familial DCM requiring heart transplantation at age 3, who also harbored the p.(Q404*) variant in trans (PMID: 19996403); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation, as the last 4 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Functional studies demonstrate a damaging effect with reduced MYBPC3 protein in a myomectomy sample from an individual with this variant (PMID: 19574547); This variant is associated with the following publications: (PMID: 36264615, 23396983, 25524337, 25525159, 18533079, 30297972, 27532257, 28254189, 31110529, 31589614, 33673806, 33087929, 33996946, 25351510, 34076677, 35626289, 36129056, 19996403, 19574547) - |
Hypertrophic cardiomyopathy;C0023976:Long QT syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Jun 05, 2018 | - - |
Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 18, 2017 | - - |
Hypertrophic cardiomyopathy 4 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000042744, PMID:18533079). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Primary familial hypertrophic cardiomyopathy Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Feb 25, 2015 | - - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 26, 2022 | The p.R1271* pathogenic mutation (also known as c.3811C>T), located in coding exon 33 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3811. This changes the amino acid from an arginine to a stop codon within coding exon 33. This alteration occurs at the 3' terminus of theMYBPC3 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 4 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been reported in individuals with hypertrophic cardiomyopathy (Olivotto I et al. Mayo Clin. Proc., 2008 Jun;83:630-8; Marston S et al. Circ. Res., 2009 Jul;105:219-22; Judge DP. JAMA, 2009 Dec;302:2471-6; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
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Uncertain
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Uncertain
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Uncertain
FATHMM_MKL
Uncertain
D
Vest4
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at