ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3697C>T (p.Gln1233Ter)

gnomAD frequency: 0.00001  dbSNP: rs397516037
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Total submissions: 22
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000168193 SCV000059261 pathogenic Hypertrophic cardiomyopathy 2019-04-05 criteria provided, single submitter clinical testing 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.
GeneDx RCV000158254 SCV000208189 pathogenic not provided 2019-11-14 criteria provided, single submitter clinical testing 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)
Invitae RCV000168193 SCV000218858 pathogenic Hypertrophic cardiomyopathy 2024-01-29 criteria provided, single submitter clinical testing 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.
Blueprint Genetics RCV000208463 SCV000264042 pathogenic Primary familial hypertrophic cardiomyopathy 2015-11-04 criteria provided, single submitter clinical testing
Center of Genomic medicine, Geneva, University Hospital of Geneva RCV000035610 SCV000292232 likely pathogenic Hypertrophic cardiomyopathy 4 2015-07-30 criteria provided, single submitter clinical testing This mutation in the MYBPC3 gene was identified in a female patient with hypertrophic cardiomyopathy.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588073 SCV000696331 pathogenic Cardiovascular phenotype 2016-06-06 criteria provided, single submitter clinical testing 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.
Ambry Genetics RCV000588073 SCV000737358 pathogenic Cardiovascular phenotype 2021-09-09 criteria provided, single submitter clinical testing 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.
Center for Human Genetics, University of Leuven RCV000168193 SCV000886773 pathogenic Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001188335 SCV001355372 pathogenic Cardiomyopathy 2021-05-18 criteria provided, single submitter clinical testing 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.
Institute of Human Genetics, University of Leipzig Medical Center RCV000035610 SCV001428646 pathogenic Hypertrophic cardiomyopathy 4 2018-07-17 criteria provided, single submitter clinical testing
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations RCV001270363 SCV001450505 pathogenic See cases 2020-12-10 criteria provided, single submitter clinical testing 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.
Clinical Genetics Laboratory, Region Ostergotland RCV000035610 SCV001984989 pathogenic Hypertrophic cardiomyopathy 4 2020-03-24 criteria provided, single submitter clinical testing PVS1, PS4, PP5, PP1
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001188335 SCV002042207 pathogenic Cardiomyopathy 2023-04-19 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000158254 SCV002103237 pathogenic not provided 2021-11-17 criteria provided, single submitter clinical testing PP1, PM2, PS4, PVS1
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health RCV000168193 SCV002522188 pathogenic Hypertrophic cardiomyopathy 2021-08-06 criteria provided, single submitter clinical testing
Human Genetics Bochum, Ruhr University Bochum RCV000168193 SCV002758620 pathogenic Hypertrophic cardiomyopathy 2022-03-31 criteria provided, single submitter clinical testing ACMG criteria used to clasify this variant: PVS1_STR, PS4, PM2_SUP, PP1, PP3
Fulgent Genetics, Fulgent Genetics RCV002482961 SCV002775432 pathogenic Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10 2021-08-06 criteria provided, single submitter clinical testing
KardioGenetik, Herz- und Diabeteszentrum NRW RCV003390723 SCV004101821 pathogenic Dilated cardiomyopathy 1I 2023-09-26 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000168193 SCV004836570 pathogenic Hypertrophic cardiomyopathy 2023-08-16 criteria provided, single submitter clinical testing This variant is predicted to result in loss of protein function through nonsense-mediated or protein truncation. Loss of function is an established mechanism of disease. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) or referred for HCM-related genetic testing (PMID: 11499719, 16715312, 18409188, 18957093, 21302287, 22455086, 25611685, 27688314, 22515980). This variant has been reported to co-segregate with HCM in multiple families (PMID: 11499719, 16199542, 16715312, 18957093). It is rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital RCV000678715 SCV000804884 pathogenic Left ventricular hypertrophy 2017-08-28 no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000158254 SCV001920537 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000158254 SCV001952191 pathogenic not provided no assertion criteria provided clinical testing

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