NM_000256.3(MYBPC3):c.3697C>T (p.Gln1233Ter) AND Cardiovascular phenotype

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 9, 2021
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:: RCV000588073.3

Allele description [Variation Report for NM_000256.3(MYBPC3):c.3697C>T (p.Gln1233Ter)]

NM_000256.3(MYBPC3):c.3697C>T (p.Gln1233Ter)

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.3697C>T (p.Gln1233Ter)

Other names:

p.Q1233*:CAG>TAG; p.Gln1233*

HGVS:

NC_000011.10:g.47332189G>A
NG_007667.1:g.25514C>T
NM_000256.3:c.3697C>TMANE SELECT
NP_000247.2:p.Gln1233Ter
LRG_386t1:c.3697C>T
LRG_386:g.25514C>T
LRG_386p1:p.Gln1233Ter
NC_000011.9:g.47353740G>A
c.3697C>T
p.(Gln1233*)
p.Gln1233X
p.Q1233*

Protein change:

Q1233*

Links:

dbSNP: rs397516037

NCBI 1000 Genomes Browser:

rs397516037

Molecular consequence:

NM_000256.3:c.3697C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000696331	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 6, 2016)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 12974739, 18409188, 15519027, 11499719, 16715312, 16199542, 18957093, 18403758, 24510615 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000737358	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (Sep 9, 2021)	germline	clinical testing	PubMed (24) [See all records that cite these PMIDs] 11499719, 15519027, 16199542, 16715312, 18409188, 18957093, 21409595, 21985754, 22455086, 24510615, 25031304, 25892673, 26271555, 27532257, 27600940, 28408708, 28615295, 29121657, 30025578, 30550750, 30847666, 31513939, 31737537, 33673806 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000696331

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jun 6, 2016)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000737358

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Pathogenic
(Sep 9, 2021)

germline

clinical testing

PubMed (24)
[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	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Mutation spectrum in a large cohort of unrelated consecutive patients with hypertrophic cardiomyopathy.

Erdmann J, Daehmlow S, Wischke S, Senyuva M, Werner U, Raible J, Tanis N, Dyachenko S, Hummel M, Hetzer R, Regitz-Zagrosek V.

Clin Genet. 2003 Oct;64(4):339-49.

PubMed [citation]

PMID:: 12974739

Shared genetic causes of cardiac hypertrophy in children and adults.

Morita H, Rehm HL, Menesses A, McDonough B, Roberts AE, Kucherlapati R, Towbin JA, Seidman JG, Seidman CE.

N Engl J Med. 2008 May 1;358(18):1899-908. doi: 10.1056/NEJMoa075463. Epub 2008 Apr 9.

PubMed [citation]

PMID:: 18403758
PMCID:: PMC2752150

See all PubMed Citations (26)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696331.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

Variant summary: The MYBPC3 c.3697C>T (p.Gln1233X) 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. One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121550 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic MYBPC3 variant (0.0010005). This variant has been reported in multiple HCM families and patients, with clear co-segregation of the variant with disease. In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, 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 Ambry Genetics, SCV000737358.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (24)

Description

The p.Q1233* pathogenic mutation (also known as c.3697C>T), located in coding exon 33 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3697. This changes the amino acid from a glutamine to a stop codon within coding exon 33. This alteration has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (HCM) and has been reported to segregate with disease in families (Erdmann J et al. J Am Coll Cardiol. 2001;38:322-30; Ingles J et al. J Med Genet. 2005;42:e59; Zeller R et al. J Mol Med. 2006;84:682-91; Ehlermann P et al. BMC Med Genet. 2008;9:95; Fokstuen S et al. Hum Mutat. 2008;29:879-85; Tóth T et al. Int J Cardiol. 2011;153:216-9; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Hathaway J et al. BMC Cardiovasc Disord, 2021 03;21:126). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.

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

Last Updated: May 7, 2024

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