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

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 18, 2023
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:: RCV001179578.7

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)

Name:: Cardiomyopathy (CMYO)
Synonyms:: Cardiomyopathies
Identifiers:: MONDO: MONDO:0004994; MedGen: C0878544; Human Phenotype Ontology: HP:0001638

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001344272	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 18, 2023)	germline	clinical testing	PubMed (20) [See all records that cite these PMIDs] 16679492, 20505798, 20624503, 22857948, 23233322, 24111713, 25335496, 27532257, 28794111, 30742251, 31006259, 31513939, 31918855, 33757590, 35470684, 36178741, 36252119, 36835444, 37963751, 25741868
SCV002042176	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 28, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003844999	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 20, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15519027, 16679492, 17612681, 24111713 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001344272

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 18, 2023)

germline

clinical testing

PubMed (20)
[See all records that cite these PMIDs]

SCV002042176

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 28, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003844999

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Feb 20, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Founder mutations in hypertrophic cardiomyopathy patients in the Netherlands.

Christiaans I, Nannenberg EA, Dooijes D, Jongbloed RJ, Michels M, Postema PG, Majoor-Krakauer D, van den Wijngaard A, Mannens MM, van Tintelen JP, van Langen IM, Wilde AA.

Neth Heart J. 2010 May;18(5):248-54.

PubMed [citation]

PMID:: 20505798
PMCID:: PMC2871745

Prevalence and spectrum of mutations in a cohort of 192 unrelated patients with hypertrophic cardiomyopathy.

Millat G, Bouvagnet P, Chevalier P, Dauphin C, Jouk PS, Da Costa A, Prieur F, Bresson JL, Faivre L, Eicher JC, Chassaing N, Crehalet H, Porcher R, Rodriguez-Lafrasse C, Rousson R.

Eur J Med Genet. 2010 Sep-Oct;53(5):261-7. doi: 10.1016/j.ejmg.2010.07.007. Epub 2010 Jul 30.

PubMed [citation]

PMID:: 20624503

See all PubMed Citations (22)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001344272.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (20)

Description

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.

#	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 CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario, SCV002042176.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003844999.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	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

Last Updated: Nov 24, 2024

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