rs397515990

chr11-47335081-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000256.3(MYBPC3):c.2864_2865del(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:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:26
• Conservation: PhyloP100: 9.51

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]

ACMG classification

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 11-47335081-CAG-C is Pathogenic according to our data. Variant chr11-47335081-CAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47335081-CAG-C is described in Lovd as [Pathogenic]. Variant chr11-47335081-CAG-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.2864_2865del	p.Pro955ArgfsTer95	frameshift_variant	27/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2864_2865del	p.Pro955ArgfsTer95	frameshift_variant	27/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.2864_2865del	p.Pro955ArgfsTer95	frameshift_variant	26/34	5		A2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000693 AC: 10 AN: 1443528 Hom.: 0 AF XY: 0.00000837 AC XY: 6 AN XY: 716840

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000907

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74360

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:26

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy 4 Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Apr 20, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Jun 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Sep 25, 2017	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 -

not provided Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jul 17, 2014	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 -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2021	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) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hypertrophic cardiomyopathy Pathogenic:5

Pathogenic, no assertion criteria provided	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Dec 12, 2019	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". -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 20, 2015	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. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 11, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Oct 31, 2018	- -

Left ventricular noncompaction 10 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jun 07, 2019	- -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Aug 15, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 02, 2021	- -

Cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 26, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 18, 2023	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 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 multiple families (PMID: 20433692, 24602869). Additionally, the variant has been reported in 2 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. -

Cardiovascular phenotype Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 24, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 20, 2017	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

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Apr 07, 2015

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Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397515990; hg19: chr11-47356632;