ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2373dup (p.Trp792fs) (rs397515963)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000162332 SCV000212628 pathogenic Familial hypertrophic cardiomyopathy 1 2014-11-25 criteria provided, single submitter research This MYBPC3 Trp792fs mutation has been well described in multiple families and individuals with HCM (Niimura H, et al., 1998; Moolman JA, et al., 2000; Erdmann J, et al., 2001; Alders M, et al., 2003). It is one of three main founder mutations in MYBPC3 in HCM patients in the Netherlands (Alders M, et al., 2003; Christianns I, et al., 2010). This Trp792fs mutation accounts for nearly 25% of all HCM cases in the Netherlands (Alders M, et al., 2003). Familial segregation (where available) shows evidence of co-segregation with disease with incomplete penetrance - a proportion of mutation carriers are mildy affected or asymptomatic (Niimura H, et al., 1998; Moolman JA, et al., 2000; Maron BJ, et al., 2001). The clinical expression associated with this variant is characterised by a late-onset HCM phenotype, and a moderate course of disease, however when symptoms develop, the phenotype is not mild. Many probands have a family history of sudden cardiac death events (Alders M, et al., 2003). There is evidence that the disease mechanism for this MYBPC3 mutation is through haploinsufficiency. Investigation of myectomy samples from MYBPC3 mutation carriers did not detect any truncated form of the MYBPC3 protein, however, the MYBPC3 protein content was significantly reduced (van Dijk SJ, et al., 2009; Marston S, et al., 2009). It has since been described by Wessels MW, et al. (2014) that compound heterozygous and homozygous truncating mutations in MYBPC3 cause neonatal lethal cardiomyopathy. We have identified this MYBPC3 Trp792fs mutation in 5 unrelated HCM patients. Based on the well described characterisation of this mutation in the literature, and in our data, we classify this variant as "pathogenic".
Ambry Genetics RCV000245146 SCV000318483 pathogenic Cardiovascular phenotype 2017-04-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Strong segregation with disease (lod >3 = >10 meioses),Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Blueprint Genetics RCV000157312 SCV000207047 pathogenic Primary familial hypertrophic cardiomyopathy 2015-10-27 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000223694 SCV000928271 pathogenic not provided 2019-03-13 criteria provided, single submitter clinical testing
Center for Human Genetics,University of Leuven RCV000198895 SCV000579520 pathogenic Hypertrophic cardiomyopathy 2017-02-09 criteria provided, single submitter clinical testing ACMG score pathogenic
Center for Medical Genetics Ghent,University of Ghent RCV000035487 SCV000299248 pathogenic Familial hypertrophic cardiomyopathy 4 2016-01-01 criteria provided, single submitter clinical testing This variant has not been identified in large population databases (Gnomad, 1000 Genomes, Go NL, Exome Variant Server) and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In addition, the variant has been reported previously in individuals with cardiomyopathy. Functional studies demonstrate that this variant causes abberrant phosphorylation of contractile proteins, reduced maximal force-generating capacity of cardiomyocytes, and enhanced Ca2+ sensitivity (PMID: 19273718 ).
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000035487 SCV000744840 pathogenic Familial hypertrophic cardiomyopathy 4 2015-09-21 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000035487 SCV000733041 pathogenic Familial hypertrophic cardiomyopathy 4 no assertion criteria provided clinical testing
GeneDx RCV000223694 SCV000208297 pathogenic not provided 2018-12-18 criteria provided, single submitter clinical testing The c.2373dupG pathogenic variant in the MYBPC3 gene has been reported in multiple individuals with HCM (Nimura et al., 1998; Michels et al., 2009; Lopes et al., 2013; Witjas-Paalberends et al., 2013; Berge et al., 2014; van Velzen et al., 2016; Walsh et al., 2017), and has been observed in multiple unrelated individuals referred for HCM genetic testing at GeneDx. It is also reported as a founder mutation in the Dutch population (Alders et al., 2003; Christiaans et al., 2010). Additionally, the c.2373dupG variant has been shown to segregate with HCM in several affected relatives from multiple families, as reported by Niimura et al. (1998) and Wessels et al. (2015), and as observed at GeneDx. This variant has also been observed in individuals with severe infantile-onset cardiomyopathy who were either homozygous for this variant or compound heterozygous for this variant and a second pathogenic variant in the MYBPC3 gene (Lekanne Deprez et al., 2006; Haberer et al., 2014; Wessels et al., 2015).The c.2373dupG variant causes a shift in reading frame starting at codon tryptophan 792, changing it to a valine, and creating a premature stop codon at position 41 of the new reading frame, denoted p.Trp792ValfsX41. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Functional studies demonstrate that c.2373dupG causes haploinsufficiency, deranged phosphorylation of contractile proteins, reduced maximal force-generating capacity of cardiomyocytes, and enhanced Ca2+ sensitivity (van Dijk et al., 2009). Moreover, multiple other downstream frameshift variants in the MYBPC3 gene have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014). Furthermore, this pathogenic variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016).
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000035487 SCV000743554 pathogenic Familial hypertrophic cardiomyopathy 4 2017-01-25 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000157312 SCV000917818 pathogenic Primary familial hypertrophic cardiomyopathy 2017-12-19 criteria provided, single submitter clinical testing Variant summary: The MYBPC3 c.2373dupG (p.Trp792ValfsX41) 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. A functional study, Van Dijk_2009, supports this variant causing loss-of-function. This variant was found in 3/166724 control chromosomes (gnomAD) at a frequency of 0.000018, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYBPC3 variant (0.0010005). Multiple publications have cited the variant in affected individuals, predominantly of Dutch origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000198895 SCV000253812 pathogenic Hypertrophic cardiomyopathy 2018-12-03 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 24 of the MYBPC3 mRNA (c.2373dupG), causing a frameshift at codon 792. This creates a premature translational stop signal (p.Trp792Valfs*41) and 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 particular variant has been reported in several individuals affected with hypertrophic cardiomyopathy (HCM), and has been shown to segregate with the disease in families (PMID: 9562578, 19273718, 22115648, 22574137). This sequence change has been reported as a common cause of HCM in individuals of Dutch ancestry, where it is reported to cause 17 to 25% of all HCM cases (PMID: 20505798, 14563344). In a study of a large multigenerational HCM family, this sequence change was shown to have reduced, age-dependent penetrance (PMID: 10736283). Additionally, neonatal cardiomyopathy with features of left ventricular non-compaction and septal defects were reported in an infant that carried this mutation in the homozygous state (PMID: 25335496). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000198895 SCV000059136 pathogenic Hypertrophic cardiomyopathy 2017-07-27 criteria provided, single submitter clinical testing The p.Trp792ValfsX41 variant in MYBPC3 has been reported in numerous individuals with HCM and has shown strong segregation with disease in multiple families (Ni imura 1998, Moolman 2000, Maron 2001, Ortlepp 2002, Alders 2003, LMM data). It h as also been identified in 3/67494 European chromosomes by the Genome Aggregatio n Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs187830361). Please note that for diseases with clinical variability and incomplete or age-dependen t penetrance, pathogenic variants may be present at a low frequency in the gener al population. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 792 and leads to a prematur e termination codon 41 amino acids downstream. Functional studies support that t his variant leads to a loss-of-function (Moolman 2000). In summary, the p.Trp792 fs variant meets criteria to be classified as pathogenic for autosomal dominant HCM based on predicted and observed impact to the protein and segregation studie s. ACMG/AMP Criteria applied: PVS1, PS4, PP1_Strong, PM2.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000223694 SCV000987547 pathogenic not provided criteria provided, single submitter clinical testing
OMIM RCV000035487 SCV000029361 pathogenic Familial hypertrophic cardiomyopathy 4 2000-03-28 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223694 SCV000280235 pathogenic not provided 2014-08-25 no assertion criteria provided clinical testing 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.Trp792ValfsX41 (c.2373dupG) in MYBPC3. Based on the data reviewed below we consider this variant very likely disease-causing. This variant is in exon 24 of the MYBPC3 gene. The c.2373dupG variant causes a shift in the reading frame beginning with Tryptophan residue 792 changing to a Valine and creating a premature stop codon at position 41 of the new reading frame. It is expected to results in an abnormal, truncated protein or in absence of protein due to mRNA decay. Nonsense and splicing variants are frequently seen in MYBPC3 in association with cardiomyopathy. To the best of our knowledge no experimental studies have demonstrated impact on splicing or the final protein product. Moolman et al (2000) were not able to identify a truncated protein product using immunohistochemistry. In total this variant has been observed in at least ~14 unrelated individuals with HCM, though three of those cases were shown to share a common founder. We have seen it in 6 families with HCM, including this patient’s family (as of October 29, 2014). Nimura et al (1998) reported this variant in 3 families with HCM. In those families 115 individuals were genotype positive for the variant; of these 45 individuals were phenotype positive for HCM. There were 10 reported disease related deaths among this group. Haplotype analysis indicated that this was a founder mutation in these 3 families. Moolman et al (2000) also described a family with HCM with this variant. A family of 49 individuals was analyzed in this publication, out of these 27 were found to be genotype positive for the variant – 10 individuals fulfilled the diagnostic criteria for HCM, 5 individuals were borderline for the disease, 12 had normal echo/ecgs and no symptoms, 2 individuals required a myectomy and 2 individuals experienced a SCD event. Alders et al (2003) reported that this variant is common in HCM patients in the Netherlands. GeneDx also reports this variant has been seen in multiple unrelated individuals tested for HCM at their laboratory(many of whom likely include our patients). This variant has been reported in multiple additional cases of HCM and (Maron et al 2001; Ortlepp et al 2002; Waldmuller et al 2002; Richard et al 2003; Van Driest et al 2004; Barr et al 2001).Some authors have suggested that this variant is associated with later onset of disease. In the kindred reported by Moolman et al (200), age of onset was late in life (often after than 30 yrs old), and Kaplan Meier survival curve illustrated near normal survival at age 50 (95%). In total the variant has not been seen in 7,200 laboratory controls, published controls and individuals from publicly available population datasets. There is no variation at codon 792 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 10/15/14). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 10/15/13). The variant was not observed in the following laboratory and published control samples: Van Driest et al (2004) did not observe the variant in 200 presumably healthy controls of unknown ancestry. Based on literature review it is unclear if the control populations used in the Niimura and Moolman publications are the same or if they represent 2 distinct groups of normal individuals-each report 100 controls. Review of a Familion/PGX testing report on the variant indicates that they did not find the variant in 400 presumably healthy control individuals (July 2009).

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