rs397516005
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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.3181C>T(p.Gln1061*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000812 in 1,600,156 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
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
MYBPC3
NM_000256.3 stop_gained
NM_000256.3 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 7.62
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 11-47333566-G-A is Pathogenic according to our data. Variant chr11-47333566-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 42690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47333566-G-A is described in Lovd as [Pathogenic]. Variant chr11-47333566-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Ensembl
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GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152264Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000836 AC: 2AN: 239364Hom.: 0 AF XY: 0.00000766 AC XY: 1AN XY: 130586
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GnomAD4 exome AF: 0.00000622 AC: 9AN: 1447892Hom.: 0 Cov.: 32 AF XY: 0.00000971 AC XY: 7AN XY: 720702
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152264Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74394
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
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 | Mar 18, 2013 | This mutation is dentoed p.Gln1061Stop (CAG>TAG): c.3181 C>T in exon 29 of the MYBPC3 gene (NM_000256.3). The Gln1061Stop mutation in the MYBPC3 gene has been reported in association with HCM (Jaaskelainen P et al., 2002). Jaaskelainen et al. identified Gln1061Stop in 6 unrelated families with HCM from Finland, and it was not observed in 200 control chromosomes. This study reported this mutation co-segregated with HCM in multiple families and suggested Gln1061Stop may be a founder mutation in the Finnish population. Gln1061Stop is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense mutations in the MYBPC3 gene have been reported in association with HCM. In summary, Gln1061Stop in the MYBPC3 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s). - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Hypertrophic cardiomyopathy Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 12, 2012 | The Gln1061X variant in MYBPC3 has been reported in the literature in six HCM pr obands, segregated in 12 affected or clinically suspicious relatives across five families and was absent from 328 healthy control chromosomes (Jaaskelaine 2002, Poutanen 2006). The families were all of Finnish ancestry, and haplotype analys is suggests that this variant could be a founder mutation in this population (Ja askelaine 2002). In addition, this variant has not been identified in large and broad populations by the NHLBI Exome Sequencing Project (http://evs.gs.washingto n.edu/EVS). Gln1061X is a nonsense variant leading to a premature termination co don at position 1061, which is predicted to lead to a truncated or absent protei n. Heterozygous loss of function of the MYBPC3 gene is an established disease me chanism in HCM patients. In summary, this variant meets our criteria to be class ified as pathogenic (http://pcpgm.partners.org/LMM) based upon segregation studi es, absence from controls, and established disease mechanism. - |
Likely pathogenic, no assertion criteria provided | research | Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 04, 2024 | This sequence change creates a premature translational stop signal (p.Gln1061*) 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 present in population databases (rs397516005, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 12110947, 26267065, 27532257). It is commonly reported in individuals of Finnish ancestry (PMID: 22462493). ClinVar contains an entry for this variant (Variation ID: 42690). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Cardiomyopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 10, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 25, 2019 | This variant changes 1 nucleotide in exon 29 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 to segregate with hypertrophic cardiomyopathy in several Finnish families (PMID: 12110947) and is thought to be a founder mutation in the Finnish population (PMID: 22462493, 30775854). This variant has also been reported in several unrelated individuals from other ethnic populations affected with hypertrophic cardiomyopathy (PMID: 19666645, 27532257, 18803133). A study has shown this variant changes the morphology, calcium handling, and electrophysiological properties in cardiomyocytes derived from an individual affected with hypertrophic cardiomyopathy (PMID: 27057166). This variant has been identified in 4/270760 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. - |
Hypertrophic cardiomyopathy 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
Primary familial hypertrophic cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Dec 08, 2015 | - - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 08, 2023 | The p.Q1061* pathogenic mutation (also known as c.3181C>T), located in coding exon 29 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3181. This changes the amino acid from a glutamine to a stop codon within coding exon 29. This is the most prevalent mutation reported to cause hypertrophic cardiomyopathy in the Finnish population and has shown a founder effect (Jääskeläinen P et al. J Mol Med (Berl). 2002;80(7):412-22; Jääskeläinen P et al. Ann Med. 2013;45(1):85-90). 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at