NM_000256.3(MYBPC3):c.2827C>T (p.Arg943Ter) AND not provided

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Jun 3, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000158189.21

Allele description [Variation Report for NM_000256.3(MYBPC3):c.2827C>T (p.Arg943Ter)]

NM_000256.3(MYBPC3):c.2827C>T (p.Arg943Ter)

Gene:

MYBPC3:myosin binding protein C3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p11.2

Genomic location:

Preferred name:

NM_000256.3(MYBPC3):c.2827C>T (p.Arg943Ter)

Other names:

p.R943*:CGA>TGA

HGVS:

NC_000011.10:g.47335120G>A
NG_007667.1:g.22583C>T
NM_000256.3:c.2827C>TMANE SELECT
NP_000247.2:p.Arg943Ter
LRG_386t1:c.2827C>T
LRG_386:g.22583C>T
LRG_386p1:p.Arg943Ter
NC_000011.9:g.47356671G>A
c.2827C>T
p.Arg943X

Protein change:

R943*; ARG943TER

Links:

OMIM: 600958.0023; dbSNP: rs387907267

NCBI 1000 Genomes Browser:

rs387907267

Molecular consequence:

NM_000256.3:c.2827C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000208124	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jun 3, 2022)	germline	clinical testing	Citation Link,
SCV000280245	Stanford Center for Inherited Cardiovascular Disease, Stanford University	no assertion criteria provided	Pathogenic (Apr 27, 2017)	germline	provider interpretation
SCV000927931	Blueprint Genetics	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme)	Pathogenic (Sep 13, 2018)	germline	clinical testing	Citation Link,
SCV001480055	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001808627	Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001919644	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001955474	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002035736	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	provider interpretation

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From GeneDx, SCV000208124.16

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280245.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	provider interpretation	not provided

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Blueprint Genetics, SCV000927931.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001480055.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		not provided	not provided	not provided	not provided

From Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus, SCV001808627.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001919644.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001955474.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus, SCV002035736.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

Relating variation to medicine