rs387907267

Positions:

• chr11-47335120-G-A

Variant summary

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

The NM_000256.3(MYBPC3):​c.2827C>T​(p.Arg943Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000013 in 1,612,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:25
• Conservation: PhyloP100: 6.30

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 11-47335120-G-A is Pathogenic according to our data. Variant chr11-47335120-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 37039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47335120-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2827C>T	p.Arg943Ter	stop_gained	27/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2827C>T	p.Arg943Ter	stop_gained	27/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.2827C>T	p.Arg943Ter	stop_gained	26/34	5		ENSP00000382193	A2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152170 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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 247124 Hom.: 0 AF XY: 0.0000223 AC XY: 3 AN XY: 134306

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000657

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1460106 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 726332

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: 0.0000930

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152170 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:25

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Sep 13, 2018	- -
Pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 27, 2017	p.Arg943Stop in the MYBPC3 gene. In total the variant has been seen in at least 18 unrelated cases with weak segregation data. This variant was initially reported in Van Driest S et al. (2004) in one individual with HCM, in the presence of another missense variant (S166F) in the TNNI3 gene (note: p.S166F in TNNI3 is also currently considered a likely disease-causing variant). The authors noted that this patient, among the other 9 with multiple mutations identified, had significantly younger age of diagnosis, the most hypertrophy, and the highest incidence of myectomy and ICD placement when compared with single mutation carriers. This variant was absent from 200 control individuals screened in their study (100 African Americans and 100 European Americans). Michels et al. 2007 reports this p.Arg943Stop variant as a Dutch founder mutation, present in 15 of 100 Netherland families with HCM. Michels et al. 2009 subsequently reports this p.Arg943Stop variant in a study performing echocardiograms in genotyped HCM patients (8 of 27 with this particular variant), mutation carriers without LVH (7 of 27 family members), and 55 controls (this variant was present in 0 of 55 controls). Note, it is unclear whether these are overlapping with the 100 families reported in this group's 2007 study. Christiaans et al. 2010 also reports this variant as a founder mutation in the Netherlands. Tajsharghi et al. 2010 reports this variant seen in homozygous form in an infant with fatal cardiomyopathy and skeletal myopathy. The patient expressed the cardiac specific MyBPC isoform in skeletal muscle at transcript and protein levels. This was a similar finding in Deprez et al. 2005, where p.Arg943Stop was identified in a neonate with severe unexplained HCM who died within the first few weeks of life, in trans with a frameshift MYBPC3 variant. GeneDx reports that this variant has also been seen in multiple other unrelated individuals tested at GeneDx. This variant also segregates with disease in the patient's own family (as it is present in him, his father, and his aunt (all of whom have HCM)). This is a nonsense variant predicted to cause loss of normal protein function either through premature protein truncation or nonsense-mediated mRNA decay. Many other truncating or 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). The variant was reported online in 3 of 122,257 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 2 of 15,313 individuals of South Asian descent (MAF=0.006%) and 1 of 55,460 individuals of European descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 01, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 03, 2022	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; Published functional studies using cardiomyocytes derived from induced pluripotent stem cells demonstrated this variant activates the nonsense-mediated decay pathway and results in aberrant calcium signaling and dysregulation of a set of other cardiac genes (Seeger et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19666645, 23674513, 25335496, 26026863, 18761664, 22569109, 28214152, 30731207, 31006259, 31918855, 31513939, 30847666, 32480058, 22574137, 16679492, 25525159, 26936621, 15519027, 19858127, 27532257, 23396983, 24510615, 22857948, 24111713, 28794111, 28396031, 28005231, 23233322, 20624503, 21839045, 19356534, 19574547, 30165862, 28797094, 29447731, 30742251, 31323898, 33673806, 32665702, 33662488, 32746448, 20505798, 30586709) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hypertrophic cardiomyopathy 4 Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 08, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Jan 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000037039 / PMID: 14563344 / 3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 02, 2022	- -

Hypertrophic cardiomyopathy Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change creates a premature translational stop signal (p.Arg943*) 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 (rs387907267, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 19574547, 20505798, 20624503, 22574137, 22857948, 23233322, 24111713, 25335496). It is commonly reported in individuals of Dutch ancestry (PMID: 19574547, 20505798, 20624503, 22574137, 22857948, 23233322, 24111713, 25335496). ClinVar contains an entry for this variant (Variation ID: 37039). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Royal Brompton Clinical Genetics And Genomics Laboratory, NHS South East Genomic Laboratory Hub	Oct 04, 2017	This variant has been reported in mutiple unrelated HCM patients in the literature (refs 1-6, below), and has also been shown to segregate with disease in multiple affected individuals in several unrelated families (Wessels et al (2015) Eur J Hum Genet 23(7)922-928). Several other clinical laboraties have also detected the variant in HCM patients referred for genetic testing (ClinVar variation ID: 37039). The variant has also been detected in control populations at a very low frequency which is compatible with the prevalence of disease (ExAC and gnomAD databases). In view of the evidence, this variant is pathogenic. - References - 1. Alders et al. (2003) Eur Heart J. 24(20):1848-53. 2. Van et al. (2004) J Am Coll Cardiol. 44(9):1903-10. 3. Christiaans et al. (2010) Neth Heart J. 18(5):248-54. 4. Millat et al. (2010) Eur J Med Genet. 53(5):261-7. 5. Yiu et al. (2012) PLoS One. 7(5):e36115. 6. Alfares et al. (2015) Genet Med.17(11):880-8. - Population Controls alleles / total (frequency): Exome Aggregation Consortium (ExAC) - 2/117632 (0.00001700), RBH healthy cohort - 0/2144 (0.0) -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2020	The p.Arg943X variant in MYBPC3 has been reported in >25 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 4 affected relatives in 4 families (Alders 2003 PMID: 14563344, Lekanne Deprez 2006 PMID: 16679492, Foksteun 2008 PMID: 18409188, Morita 2008 PMID: 18403758, Michels 2009 PMID: 19356534, Van Driest 2004 PMID: 15519027, Tajsharghi 2010 PMID: 19858127, Yiu 2012 PMID: 22574137, Wessels 2014 PMID: 25335496, LMM unpublished data). Several of these individuals carried an additional clinically significant variant and presented with early onset disease. This variant has been reported by other clinical laboratories in ClinVar (Variation ID 37039) and has also been identified in 0.006% (2/30444) of South Asian chromosomes by gnomAD (https://gnomad.broadinstitute.org/). This nonsense variant leads to a premature termination codon at position 943, which is predicted to lead to a truncated or absent protein. Loss of function of the MYBPC3 gene is an established disease mechanism in autosomal dominant HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PVS1, PS4, PP1, PM2_supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 22, 2024	This variant changes 1 nucleotide in exon 27 of the MYBPC3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Functional RNA studies using cardiac tissue derived from a heterozygous carrier individual have shown that this variant causes a significant reduction in MYBPC3 mRNA levels (PMID: 33757590). This variant has been observed in over 20 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 16679492, 20624503, 22857948, 23233322, 24111713, 25335496, 27532257, 31006259, 31513939, 33757590, 36252119, 36835444) and is considered to be a founder mutation in the Dutch population (PMID: 20505798, 28794111). This variant has been reported to cause lethal cardiomyopathy or severe neonatal hypertrophic cardiomyopathy in individuals who were homozygous or compound heterozygous with another pathogenic mutation (PMID: 16679492, 24111713, 25335496, 30742251, 36178741). It has also been reported in two individuals affected with left ventricular noncompaction who both carried an additional different pathogenic variant (PMID: 31918855, 37963751), and in one individual affected with atrioventricular block (PMID: 35470684). This variant has been identified in 3/247124 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics	-	- -

Cardiomyopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 20, 2023	Variant summary: MYBPC3 c.2827C>T (p.Arg943X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 247124 control chromosomes (gnomAD). c.2827C>T has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Van Driest_2004, Deprez_2006, Michels_2007, Berge_2013). These data indicate that the variant is very likely to be associated with disease. 15 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 28, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 18, 2023	This variant changes 1 nucleotide in exon 27 of the MYBPC3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Functional RNA studies using cardiac tissue derived from a heterozygous carrier individual have shown that this variant causes a significant reduction in MYBPC3 mRNA levels (PMID: 33757590). This variant has been observed in over 20 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 16679492, 20624503, 22857948, 23233322, 24111713, 25335496, 27532257, 31006259, 31513939, 33757590, 36252119, 36835444) and is considered to be a founder mutation in the Dutch population (PMID: 20505798, 28794111). This variant has been reported to cause lethal cardiomyopathy or severe neonatal hypertrophic cardiomyopathy in individuals who were homozygous or compound heterozygous with another pathogenic mutation (PMID: 16679492, 24111713, 25335496, 30742251, 36178741). It has also been reported in two individuals affected with left ventricular noncompaction who both carried an additional different pathogenic variant (PMID: 31918855, 37963751), and in one individual affected with atrioventricular block (PMID: 35470684). This variant has been identified in 3/247124 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 24, 2021

The p.R943* pathogenic mutation (also known as c.2827C>T) located in coding exon 27 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2827. This changes the amino acid from an arginine to a stop codon within coding exon 27. This mutation has been reported in multiple unrelated probands with hypertrophic cardiomyopathy, having been reported as a Dutch founder mutation (Van Driest SL et al. J Am Coll Cardiol. 2004; 44(9):1903-10; Michels M et al. Neth Heart J. 2007;15(5):184-90; Michels M et al. JACC Cardiovasc Imaging. 2009;2(1):58-64; Christiaans I et al. Neth Heart J. 2010;18(5):248-54; Brito D et al. Rev Port Cardiol. 2012;31(9):577-87; Hathaway J et al. BMC Cardiovasc Disord, 2021 03;21:126). This mutation has been reported as occurring in the homozygous state and also with other alterations in patients with severe, early onset disease with and without other findings such as skeletal myopathy, non-compaction and congenital heart defects (Lekanne Deprez RH et al. J Med Genet. 2006;43(10):829-32; Tajsharghi H et al. J Med Genet. 2010;47(8):575-7; Berge KE et al. Clin Genet. 2014;86(4):355-60; Wessels MW et al. Eur J Hum Genet. 2015;23(7):922-8; van Velzen HG et al. Circ Cardiovasc Genet, 2017 Aug;10:[Epub ahead of print]). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.90
GERP RS		5.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs387907267; hg19: chr11-47356671; COSMIC: COSV57023485; COSMIC: COSV57023485;