NM_000256.3:c.2864_2865delCT
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000256.3(MYBPC3):c.2864_2865delCT(p.Pro955ArgfsTer95) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000689 in 1,595,750 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000256.3 frameshift
Scores
Clinical Significance
Conservation
Publications
- hypertrophic cardiomyopathyInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- hypertrophic cardiomyopathy 4Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
- left ventricular noncompaction 10Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- arrhythmogenic right ventricular cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
- atrial fibrillationInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
- dilated cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MYBPC3 | NM_000256.3 | c.2864_2865delCT | p.Pro955ArgfsTer95 | frameshift_variant | Exon 27 of 35 | ENST00000545968.6 | NP_000247.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYBPC3 | ENST00000545968.6 | c.2864_2865delCT | p.Pro955ArgfsTer95 | frameshift_variant | Exon 27 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
| MYBPC3 | ENST00000399249.6 | c.2864_2865delCT | p.Pro955ArgfsTer95 | frameshift_variant | Exon 26 of 34 | 5 | ENSP00000382193.2 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.00 AC: 0AN: 232748 AF XY: 0.00
GnomAD4 exome AF: 0.00000693 AC: 10AN: 1443528Hom.: 0 AF XY: 0.00000837 AC XY: 6AN XY: 716840 show subpopulations
Age Distribution
GnomAD4 genome 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74360 show subpopulations
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy 4 Pathogenic:8
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Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene (PMID: 28771489). (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 27 of 35). (P) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD (v3) <0.001 (1 heterozygote, 0 homozygotes). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Many other NMD-predicted variants in MYBPC3 have previously been reported as pathogenic (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This recurrent variant has previously been reported as pathogenic in multiple patients, both at VCGS and externally, and has been shown to segregate in families with autosomal dominant hypertrophic cardiomyopathy (ClinVar, PMID: 9562578, PMID: 28615295). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
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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 -
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Hypertrophic cardiomyopathy Pathogenic:6
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. -
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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". -
This variant deletes 2 nucleotides in exon 27 of the MYBPC3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (HCM)(PMID: 12707239, 19273718, 20433692, 20505798, 22115648, 24602869, 32841044). It has been shown that this variant segregates with disease in families (PMID: 20433692, 24602869). Additionally, the variant has been reported in 2 individuals affected with left ventricular noncompaction (LVNC) (PMID: 21551322, 24602869). This variant has not been identified 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. -
This sequence change creates a premature translational stop signal (p.Pro955Argfs*95) 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 (rs397515990, gnomAD 0.0008%). This premature translational stop signal has been observed in individuals 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. -
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not provided Pathogenic:5
Published functional study demonstrated that this deletion alters calcium sensitivity and the force-generating capacity of muscle cells (van Dijk et al. 2009); Frameshift 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; This variant is associated with the following publications: (PMID: 22569109, 24602869, 31513939, 31737537, 23549607, 22115648, 19356534, 21257752, 9562578, 27532257, 26914223, 19574547, 21551322, 26671970, 28794111, 28615295, 28214152, 29121657, 25351510, 20505798, 19273718, 30847666, 32480058, 27600940, 26090888, 25335496, 24793961, 24510615, 21252143, 33662488, 34540771, 31589614, 26582918, 33673806, 34135346) -
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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 varian -
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Left ventricular noncompaction 10 Pathogenic:2
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Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Pathogenic:2
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The c.2864_2865del, p.(Pro955ArgfsTer95) variant identified in the MYBPC3 gene is a deletion of two nucleotides within exon 27/35 which leads to a frameshift of the protein at amino acid 955/1275, and is predicted to lead to the premature termination of the protein approximately 95 amino acids downstream. This variant is found with low frequency in population databases gnomADv2.1.1, gnomADv3.1.2, TOPMed Freeze 8, All of Us (allele frequency=6.80e-6) suggesting it is not a common benign variant in the populations represented in those databases. This variant is reported as Pathogenic/Likely Pathogenic in ClinVar(VarID:42663) and has been reported in many individuals in the literature with cardiomyopathy [PMID:19273718, 20433692, 24510615, others]. Given its deleterious nature, low frequency in population databases, and observation in multiple affected individuals in the literature, the c.2864_2865del,p.(Pro955ArgfsTer95) variant identified in the MYBPC3 gene is reported as Pathogenic. -
Cardiomyopathy Pathogenic:2
This variant deletes 2 nucleotides in exon 27 of the MYBPC3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 19273718, 20433692, 22115648, 24602869, 34542152, 34680864, 35288587, 35626289, 35653365, 36166435). It has been shown that this variant segregates with disease in multiple families (PMID: 20433692, 24602869, 34680864). Additionally, the variant has been reported in two individuals affected with left ventricular noncompaction (PMID: 21551322, 24602869). This variant has not been identified 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. -
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Cardiovascular phenotype Pathogenic:2
The c.2864_2865delCT pathogenic mutation, located in coding exon 27 of the MYBPC3 gene, results from a deletion of two nucleotides at nucleotide positions 2864 to 2865, causing a translational frameshift with a predicted alternate stop codon (p.P955Rfs*95). This alteration has been reported in multiple patients with hypertrophic cardiomyopathy (Niimura H et al. N Engl J Med. 1998;338(18):1248-57 (reported as delCT955); Marston S et al. Circ Res. 2009;105(3):219-22; Christiaans I et al. Neth Heart J. 2010;18(5):248-54; Schaefer E et al. Eur J Med Genet. 2014;57(4):129-32; van Dijk SJ et al. Circulation. 2009;119(11):1473-83), and has been reported to cause reduced mRNA and protein expression (van Dijk SJ et al. Circulation. 2009;119(11):1473-83). 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. -
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. -
Primary familial hypertrophic cardiomyopathy Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at