rs397516037
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000256.3(MYBPC3):c.3697C>T(p.Gln1233*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,506 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: not found (cov: 33)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
MYBPC3
NM_000256.3 stop_gained
NM_000256.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 7.75
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 11-47332189-G-A is Pathogenic according to our data. Variant chr11-47332189-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47332189-G-A is described in Lovd as [Pathogenic]. Variant chr11-47332189-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.00000802 AC: 2AN: 249238Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135218
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GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461506Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10AN XY: 727046
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:23
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:6
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, University of Leuven | Oct 31, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 27, 2024 | This variant changes 1 nucleotide in exon 33 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 25 individuals affected with hypertrophic cardiomyopathy (PMID: 11499719, 18957093, 21985754, 24510615, 25031304, 25351510, 27600940, 27532257, 28615295, 33495596, 33495597, 33673806, 34542152, 34598319, 35176171, 38002985, 38540378). This variant has been identified in 2/249238 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 | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 05, 2019 | The p.Gln1233X variant has been reported in >10 families with HCM and segregated with disease in >10 affected relatives (Erdmann 2001, Ingles 2005, Zeller 2006, Ehlermann 2008, LMM data). This variant has been reported in ClinVar: P (GeneDx, Invitae, Blueprint, Integrated, Ambry, Johns Hopkins), LP (Geneva).This variant has also been identified in 1/66626 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397516037). This nonsense variant leads to a premature termination codon at position 1233, which is predicted to lead to a truncated or absent protein. Nonsense and other MYBPC3 variants resulting in a heterozygous loss of function are strongly associated with HCM. In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genetics Bochum, Ruhr University Bochum | Mar 31, 2022 | ACMG criteria used to clasify this variant: PVS1_STR, PS4, PM2_SUP, PP1, PP3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change creates a premature translational stop signal (p.Gln1233*) 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 (rs397516037, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 11499719, 18957093, 21985754). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42735). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health | Aug 06, 2021 | - - |
not provided Pathogenic:5
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 14, 2019 | 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 (ClinVar Variant ID# 42735; ClinVar); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22515980, 27688314, 12974739, 31513939, 18761664, 21415409, 25163546, 25351510, 17655857, 25525159, 25031304, 18409188, 11499719, 16199542, 18403758, 15519027, 18957093, 21302287, 18505755, 16715312, 21985754, 27662471, 27532257, 28615295, 28408708, 28790153, 24510615, 27600940, 30025578, 29121657, 30550750, 31737537, 30847666, 33673806) - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | MYBPC3: PVS1, PP1:Strong, PS4:Moderate, PM2:Supporting, PP4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 17, 2021 | PP1, PM2, PS4, PVS1 - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Hypertrophic cardiomyopathy 4 Pathogenic:3
| Likely pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Jul 30, 2015 | This mutation in the MYBPC3 gene was identified in a female patient with hypertrophic cardiomyopathy. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Region Ostergotland | Mar 24, 2020 | PVS1, PS4, PP5, PP1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jul 17, 2018 | - - |
Cardiomyopathy Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 19, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 18, 2021 | This variant changes 1 nucleotide in exon 33 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 individuals affected with hypertrophic cardiomyopathy (PMID: 11499719, 18957093, 21985754, 24510615, 25031304, 25351510, 27600940, 27532257, 28615295). This variant has been identified in 2/249238 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. - |
Cardiovascular phenotype Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 09, 2021 | The p.Q1233* pathogenic mutation (also known as c.3697C>T), located in coding exon 33 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3697. This changes the amino acid from a glutamine to a stop codon within coding exon 33. This alteration has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (HCM) and has been reported to segregate with disease in families (Erdmann J et al. J Am Coll Cardiol. 2001;38:322-30; Ingles J et al. J Med Genet. 2005;42:e59; Zeller R et al. J Mol Med. 2006;84:682-91; Ehlermann P et al. BMC Med Genet. 2008;9:95; Fokstuen S et al. Hum Mutat. 2008;29:879-85; Tóth T et al. Int J Cardiol. 2011;153:216-9; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Hathaway J et al. BMC Cardiovasc Disord, 2021 03;21:126). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 06, 2016 | Variant summary: The MYBPC3 c.3697C>T (p.Gln1233X) variant results in a premature termination codon, predicted to cause a truncated or absent MYBPC3 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121550 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYBPC3 variant (0.0010005). This variant has been reported in multiple HCM families and patients, with clear co-segregation of the variant with disease. In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Dilated cardiomyopathy 1I Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | KardioGenetik, Herz- und Diabeteszentrum NRW | Sep 26, 2023 | - - |
Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 06, 2021 | - - |
See cases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations | Dec 10, 2020 | We observed the genetic variant c.3697C>T (p.Q1233*) in MYBPC3 gene in several probands, diagnosed with various cardiomyopathies. The c.3697C>T variant was previously described as pathogenic (PP5 criteria). IT leads to premature stop-codon at 1233 amino acid position in MYBPC3 gene. Nonsense mutations are a well-known cause of MYBPC3-related cardiomyopathies, therefore, PVS1 criteria is applicable for c.3697C>T variant. The c.3697C>T variant has low frequency in large population studies (PM2 criteria). Several online in silico tools predict the c.3697C>T variant to be deleterious (PP3 criteria). Based on these criteria, we consider the c.3697C>T (p.Q1233*) variant to be pathogenic. - |
Primary familial hypertrophic cardiomyopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Nov 04, 2015 | - - |
Left ventricular hypertrophy Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Aug 28, 2017 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
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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