ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2864_2865del (p.Pro955fs) (rs397515990)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000225856 SCV000059183 pathogenic Hypertrophic cardiomyopathy 2015-02-20 criteria provided, single submitter clinical testing The p.Pro955fs variant in MYBPC3 has been identified in >20 individuals with HCM and has segregated with disease in >10 individuals across multiple families (Ch ristiaans 2010, Marston 2009, Nannenberg 2011, Niimuri 1998, Probst 2011, Richar d 2003, Rodriguez-Garcia 2010, van Dijk 2009, LMM unpublished data). This varian t has also been reported in two individuals with LVNC, both of whom carried a se cond pathogenic variant in MYBPC3 (Probst 2011, Schaefer 2014). This variant was also absent from large population studies. This frameshift variant is predicted to alter the protein?s amino acid sequence beginning at position 955 and lead t o a premature termination codon 95 amino acids downstream. This alteration is th en predicted to lead to a truncated or absent protein. Heterozygous loss of MYBP C3 function is an established disease mechanism in individuals with HCM. In summ ary, this variant meets our criteria to be classified as pathogenic for HCM in a n autosomal dominant manner (http://www.partners.org/personalizedmedicine/LMM) b ased upon segregation studies and its predicted impact on the protein.
GeneDx RCV000158381 SCV000208316 pathogenic not provided 2018-07-02 criteria provided, single submitter clinical testing The c.2864_2865delCT variant in the MYBPC3 gene causes a frameshift beginning with codon Proline 955, changing it to an Arginine residue, and creating a premature stop codon at position 95 of the new reading frame, denoted p.Pro955ArgfsX95. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.2864_2865delCT variant has been identified in several unrelated individuals tested for hypertrophic cardiomyopathy (HCM) at GeneDx and has also been reported multiple times in the published literature in association with HCM (Niimura et al., 1998; van Dijk et al., 2009; Marston et al., 2009; Christiaans et al., 2010). This deletion was reported to co-segregate with HCM in a large family, in which 2 out of 4 individuals under 20 years of age and 6 out of 8 individuals above 20 years of age with this variant had clinical signs of HCM (Niimura et al., 1998). Subsequently, c.2864_2865delCT was identified in 12/735 (1.6%) Dutch individuals with HCM, and is likely a founder or recurrent mutation (Christiaans et al., 2010; Ross et al., 2017). Additionally, one functional study indicated that MYBPC3 frameshift variants result in haploinsufficiency, with this deletion altering calcium sensitivity and the force-generating capacity of muscle cells (van Dijk et al., 2009). Finally, it should be noted that the c.2864_2865delCT variant was not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.2864_2865delCT as a pathogenic variant.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000035533 SCV000256180 likely pathogenic Familial hypertrophic cardiomyopathy 4 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000208060 SCV000264057 pathogenic Primary familial hypertrophic cardiomyopathy 2015-04-07 criteria provided, single submitter clinical testing
Invitae RCV000225856 SCV000284234 pathogenic Hypertrophic cardiomyopathy 2019-12-20 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotides from exon 27 of the MYBPC3 mRNA (c.2864_2865delCT), causing a frameshift at codon 955. This creates a premature translational stop signal (p.Pro955Argfs*95) and is expected to result in an absent or disrupted protein product. Truncating variants in MYBPC3 are known to be pathogenic. This particular truncation has been reported in the literature in multiple unrelated patients with hypertrophic cardiomyopathy (PMID: 19273718, 20433692, 21551322). ClinVar contains an entry for this variant (Variation ID: 42663). For these reasons, this variant has been classified as Pathogenic.
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000035533 SCV000693467 pathogenic Familial hypertrophic cardiomyopathy 4 2017-09-25 criteria provided, single submitter clinical testing This heterozygous frameshift variant in the MYBPC3 gene was identified in three members of the same family: the father, the daughter and the son. Both the father and the daughter were diagnosed with obstructive hypertrophic cardiomyopathy
Integrated Genetics/Laboratory Corporation of America RCV000589120 SCV000696326 pathogenic Cardiovascular phenotype 2017-06-20 criteria provided, single submitter clinical testing Variant summary: The MYBPC3 c.2864_2865delCT (p.Pro955Argfs) 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. This variant is absent in 108262 control chromosomes. Multiple publications have cited this variant in affected individuals including its cosegregation with disease in a large HCM family (Niimura_1998). The variant of interest has been indicated to be a Dutch founder mutation (Christiaans_2010). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Ambry Genetics RCV000589120 SCV000737349 pathogenic Cardiovascular phenotype 2018-12-12 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000035533 SCV000743546 pathogenic Familial hypertrophic cardiomyopathy 4 2014-10-10 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000035533 SCV000744833 pathogenic Familial hypertrophic cardiomyopathy 4 2015-09-21 criteria provided, single submitter clinical testing
Center for Human Genetics,University of Leuven RCV000225856 SCV000886767 pathogenic Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
Institute of Human Genetics,Klinikum rechts der Isar RCV000054803 SCV001429937 pathogenic Left ventricular noncompaction 10 2019-06-07 criteria provided, single submitter clinical testing
OMIM RCV000054803 SCV000083048 pathogenic Left ventricular noncompaction 10 2011-08-01 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158381 SCV000280249 pathogenic not provided 2014-07-17 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.Pro955ArgfsX95 (c.2864_2865delCT) in the MYBPC3 gene. Based on the data reviewed below we consider it very likely disease causing. This variant has been seen in at least 8 unrelated individuals (not including this patient) with HCM with strong co-segregation data in multiple families. It has also been reported as a founder variant in the Netherlands. Niimura et al reported a large family in which all 8 genotyped affected family members had this variant. Richard et al (2003) observed the variant in one individual in their French cohort. Marston et al (2009) reported one patient with this variant and HCM from their British cohort. van Dijk et al (2009) reported on four patients with this variant from their Dutch cohort. The authors do not note whether these individuals are related to each other, though they do describe the variant as a founder mutation. A dutch group has reported this variant as a Dutch founder, observing it in 12 Dutch individuals with HCM (Michels et al 2007, Christiaans et al 2010). Probst et al (2011) observed the variant in a patient with left ventricular non-compaction from their Swiss and German cohort. Millat et al (2010) reported the variant in one patient with HCM from their French cohort (this appears to be a different case from that reported by Richards et al). Rodríguez-García et al (2010) observed the variant in a family in their spanish cohort with 15 family members with HCM carrying the variant. We have seen this variant in one other individual with HCM in our center. GeneDx also notes they have seen this variant in multiple other unrelated cases of HCM tested in their lab (one of those is our other HCM patient with this variant). In addition to changing a Proline at residue 955 to an Arginine, this two-nucleotide deletion causes a shift in the reading frame and creates a premature stop codon 95 codons downstream. Variants of this type are expected to either create a truncated protein or lead to complete absence of the protein due to mRNA decay. van Dijk et al (2009) studied myectomy samples from patients with p.Pro955ArgfsX95 and compared them to non-failing donor heart tissue. They found that mutant mRNA represented 20% of total MYBPC3 mRNA. Western blots did not detect a truncated protein but did detect a reduction in total protein. They also observed a decrease in troponin I phosphorylation, decreased maximal force per cross sectional area of cardiomyocytes, and higher calcium sensitivity. In a similar study Martson et al (2009) compared myectomy samples from patients with MYBPC3 variants, healthy donor hearts, and HCM patients who did not have MYBPC3 variants. Samples from a patient with p.Pro955ArgfsX95 showed reduced myosin binding protein levels relative to actin (and relative to controls and other HCM patiens) with no truncated protein product identified. Many other frameshift and null variants have been identified in MYBPC3 in association with cardiomyopathy (ex. p.Trp792fs, p.Pro794fs, p.Lys1065fs, p.Cys1202fs, p.Pro1208fs, p.Trp1098ter, p.Glu1096ter, p.Cys1124ter, p.Gln1233ter). Furthermore, these types of variants in MYBPC3 are not seen in individuals without cardiomyopathy (Pan et al 2012). In total the variant has not been seen in ~7280 published controls and individuals from publicly available population datasets. The variant is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of April 19th, 2013). Of note only 1 of 6500 individuals in that dataset have a MYBPC3 frameshift variant. The variant is not listed in dbSNP or 1000 genomes (as of April 19th, 2013). The variant was not observed in the following laboratory and published control samples: 100 presumably healthy individuals of unspecified ancestry (Niimura et al 2008), 100 controls (Richard et al 2003), 180 controls (Probst et al 2011), 400 controls (Rodríguez-García et al 2010). GeneDx did not report control data
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000035533 SCV000733033 pathogenic Familial hypertrophic cardiomyopathy 4 no assertion criteria provided clinical testing
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000225856 SCV001430863 pathogenic Hypertrophic cardiomyopathy 2019-12-12 no assertion criteria provided research The MYBPC3 Pro955Argfs*95 has been seen in many HCM probands, is a well established Dutch Founder and has been reported to segregate in several families. A study comparing contractile performance in cardiac muscle samples showed that Pro955Argfs*95 reduced cMyBPC protein levels. This lowered protein level resulted in a decline in the maximum force of the cells and correlated to reduced protein expression consequently altering calcium homeostasis and phospholyration (van Dijk SJ, et al., 2009). This variant is absent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We have identified this variant in 9 HCM probands (Ingles et al., 2017; Ross et al., 2017; Ingles et al., 2015). Based on the adapted ACMG guidelines (Kelly et al., 2018), this variant results in loss of function of MYBPC3 (PVS1), has been reported in more than 15 HCM probands (PS4), cosegregates with HCM in families (PP1_strong) and is rare in the general population (PM2), therefore we classify MYBPC3 Pro955Argfs*95 as "pathogenic".

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