NC_000011.10:g.47337730dup AND Hypertrophic cardiomyopathy

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Jan 13, 2024
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:: RCV000198895.26

Allele description [Variation Report for NC_000011.10:g.47337730dup]

NC_000011.10:g.47337730dup

Gene:

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

Variant type:

Duplication

Cytogenetic location:

11p11.2

Genomic location:

Preferred name:

NC_000011.10:g.47337730dup

Other names:

p.Trp792ValfsX41; p.Trp792Valfs*41

HGVS:

NC_000011.10:g.47337730dup
NG_007667.1:g.19973dup
NM_000256.3:c.2373dupMANE SELECT
NM_000256.3:c.2373dupG
NP_000247.2:p.Trp792fs
LRG_386t1:c.2373dup
LRG_386:g.19973dup
LRG_386p1:p.Trp792fs
NC_000011.10:g.47337729_47337730insC
NC_000011.9:g.47359281dup
NM_000256.3:c.2372_2373insGMANE SELECT
NM_000256.3:c.2373dupGMANE SELECT
c.2373_2374insG
p.W792VfsX41

Protein change:

W792fs

Links:

OMIM: 600958.0011; dbSNP: rs397515963

NCBI 1000 Genomes Browser:

rs397515963

Observations:

Condition(s)

Name:: Hypertrophic cardiomyopathy
Synonyms:: HYPERTROPHIC MYOCARDIOPATHY
Identifiers:: MONDO: MONDO:0005045; MeSH: D002312; MedGen: C0007194; Human Phenotype Ontology: HP:0001639

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000059136	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 3, 2022)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 9562578, 10736283, 11499718, 11847170, 14563344, 19574547, 19273718, 20505798, 22115648, 25335496, 22574137, 29300372, 25741868
SCV000212628	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	no assertion criteria provided	Pathogenic (Mar 24, 2020)	germline	research	PubMed (11) [See all records that cite these PMIDs] 9562578, 10736283, 14563344, 11499719, 25335496, 19356534, 19273718, 20505798, 19574547, 11499718, 27532257
SCV000253812	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 13, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 19574547, 9562578, 10736283, 19273718, 22115648, 22574137, 25335496, 14563344, 20505798, 28492532
SCV000579520	Center for Human Genetics, University of Leuven	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 9, 2017)	germline	clinical testing
SCV001572570	Loeys Lab, Universiteit Antwerpen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 26, 2021)	paternal	clinical testing	PubMed (10) [See all records that cite these PMIDs] 9562578, 10736283, 14563344, 19356534, 23674513, 24111713, 27476098, 25335496, 19273718, 25741868
SCV004842354	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 5, 2024)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 9562578, 10736283, 14563344, 19273718, 20505798, 22115648, 22574137, 25335496, 32880476, 35653365, 25741868
SCV005374562	Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics	no assertion criteria provided	Pathogenic	unknown	research

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	not provided	not provided	research
not provided	germline	unknown	5	not provided	not provided	108544	not provided	clinical testing
not provided	paternal	yes	8	2	not provided	18	yes	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	research
Caucasian	germline	yes	14	8	not provided	not provided	yes	clinical testing

Citations

PubMed

Genetic polymorphisms in the renin-angiotensin-aldosterone system associated with expression of left ventricular hypertrophy in hypertrophic cardiomyopathy: a study of five polymorphic genes in a family with a disease causing mutation in the myosin binding protein C gene.

Ortlepp JR, Vosberg HP, Reith S, Ohme F, Mahon NG, Schröder D, Klues HG, Hanrath P, McKenna WJ.

Heart. 2002 Mar;87(3):270-5.

PubMed [citation]

PMID:: 11847170
PMCID:: PMC1767035

Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen's Inherited Cardiomyopathy Expert Panel.

Kelly MA, Caleshu C, Morales A, Buchan J, Wolf Z, Harrison SM, Cook S, Dillon MW, Garcia J, Haverfield E, Jongbloed JDH, Macaya D, Manrai A, Orland K, Richard G, Spoonamore K, Thomas M, Thomson K, Vincent LM, Walsh R, Watkins H, Whiffin N, et al.

Genet Med. 2018 Mar;20(3):351-359. doi: 10.1038/gim.2017.218. Epub 2018 Jan 4.

PubMed [citation]

PMID:: 29300372
PMCID:: PMC5876064

See all PubMed Citations (22)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059136.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

The p.Trp792ValfsX41 variant in MYBPC3 has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM) and has shown strong segregation with disease in multiple families (Niimura 1998 PMID: 9562578, Moolman 2000 PMID: 10736283, Maron 2001 PMID: 11499718, Ortlepp 2002 PMID: 11847170, Alders 2003 PMID: 14563344, Walsh 2017 PMID: 27532257, LMM data). This variant a likely Dutch founder variant and is estimated to account for approximately 25% of cases of HCM in the Netherlands (Alders 2003 PMID: 14563344). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 42619) and has been identified in 0.004% (3/70142) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Please note that for diseases with clinical variability and incomplete or age-dependent penetrance, pathogenic variants may be present at a low frequency in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 792 and leads to a premature termination codon 41 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In vitro functional studies support that this variant leads to a loss-of-function (Moolman 2000 PMID: 10736283). Heterozygous 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_Strong, PM2_Supporting.

#	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 Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, SCV000212628.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (11)

Description

MYBPC3 Trp792fs has been well described in multiple families and individuals with HCM (see literature). It is one of three main founder mutations in MYBPC3 in HCM patients in the Netherlands (Alders M, et al., 2003; Christianns I, et al., 2010). This Trp792fs mutation accounts for nearly 25% of all HCM cases in the Netherlands (Alders M, et al., 2003). Familial segregation (where available) shows evidence of co-segregation (Niimura H, et al., 1998; Moolman JA, et al., 2000; Maron BJ, et al., 2001). The variant is present at a low frequency in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We have identified this MYBPC3 Trp792fs mutation in 12 unrelated HCM probands and the variant has been found to segregate with disease in several of our families. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018), this variant results in loss of function of MYBPC3 (PVS1), has been identified in well over 15 HCM probands (PS4), segregates strongly with disease (PP1_strong) and is rare in the general population (PM2), therefore we classify MYBPC3 Trp792fs as 'pathogenic'.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000253812.13

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change creates a premature translational stop signal (p.Trp792Valfs*41) 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 (rs397515963, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (HCM) or neonatal cardiomyopathy with features of left ventricular non-compaction and septal defects (PMID: 9562578, 10736283, 19273718, 22115648, 22574137, 25335496). It is commonly reported in individuals of Dutch ancestry (PMID: 14563344, 20505798). ClinVar contains an entry for this variant (Variation ID: 42619). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.

#	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 Center for Human Genetics, University of Leuven, SCV000579520.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	14	not provided	yes	clinical testing	not provided

Description

ACMG score pathogenic

#	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		14	not provided	8	not provided

From Loeys Lab, Universiteit Antwerpen, SCV001572570.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	8	not provided	yes	clinical testing	PubMed (10)

Description

This sequence change results in a frameshift variant in the MYBPC3 gene (p.(Trp792ValFs*41)) resulting in loss-of function and haploinsufficiency, which is a known disease mechanism(PVS1) (PMID: 19273718). This variant is present in population databases (GnomAD 3/166724). This variant has been reported in the literature in several families with HCM and showed co-seggregation with HCM (PP1strong) (PMID:9562578; PMID: 10736283; PMID: 14563344; PMID: 19356534; PMID: 23674513; PMID: 24111713; PMID: 27476098; PMID:25335496).It has been described as a Dutch Founder variant, present in 17-25% of all HCM cases (PS4) (PMID: 20505798, 14563344).Functional studies demonstrated that the variant reduced maximal force-generating capacity of cardiomyocytes(PS3) (PMID: 19273718). We identified this variant in two HCM families. In conclusion this variant was classified as a pathogenic variant according to ACMG-guidelines (PVS1; PP1strong; PS4;PS3).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	paternal	yes	18	blood	not provided		8	not provided	2	not provided

From All of Us Research Program, National Institutes of Health, SCV004842354.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (11)

Description

This variant inserts 1 nucleotide in exon 24 of the fibronectin type 3 domain C6 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. RNA studies has shown that this variant may create a new splice donor site, which could also result in a frameshift and premature truncation (PMID: 10736283). This variant has been reported in over 300 individuals affected with hypertrophic cardiomyopathy (PMID: 9562578, 14563344, 19273718, 20505798, 22115648, 22574137, 35653365) and occurs in up to 25% of Dutch individuals affected with hypertrophic cardiomyopathy (PMID: 14563344, 20505798). A study of a large multigenerational family affected with hypertrophic cardiomyopathy has shown that penetrance of this variant is incomplete and age-dependent (PMID: 10736283). This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 32880476), and it has also been reported in compound heterozygous or homozygous state in three Dutch neonates with lethal cardiomyopathy (PMID: 25335496). This variant has been identified in 3/172018 chromosomes 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		5	not provided	not provided	not provided

From Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics, SCV005374562.1

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

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

Last Updated: Nov 24, 2024

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