NM_000256.3(MYBPC3):c.2182G>T (p.Glu728Ter) AND Hypertrophic cardiomyopathy

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 19, 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:: RCV000768471.13

Allele description [Variation Report for NM_000256.3(MYBPC3):c.2182G>T (p.Glu728Ter)]

NM_000256.3(MYBPC3):c.2182G>T (p.Glu728Ter)

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.2182G>T (p.Glu728Ter)

Other names:

p.E728*:GAG>TAG

HGVS:

NC_000011.10:g.47338646C>A
NG_007667.1:g.19057G>T
NM_000256.3:c.2182G>TMANE SELECT
NP_000247.2:p.Glu728Ter
LRG_386t1:c.2182G>T
LRG_386:g.19057G>T
LRG_386p1:p.Glu728Ter
NC_000011.9:g.47360197C>A
c.2182G>T
p.Glu728X

Protein change:

E728*

Links:

dbSNP: rs397515954

NCBI 1000 Genomes Browser:

rs397515954

Molecular consequence:

NM_000256.3:c.2182G>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000059121	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Jun 4, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24810389, 27532257, 24033266
SCV000886757	Center for Human Genetics, University of Leuven	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001417126	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 19, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19574547, 27532257, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000059121

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Jun 4, 2018)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV000886757

Center for Human Genetics, University of Leuven

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 31, 2018)

germline

clinical testing

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

SCV001417126

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 19, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	2	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	11	4	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Significance of left ventricular apical-basal muscle bundle identified by cardiovascular magnetic resonance imaging in patients with hypertrophic cardiomyopathy.

Gruner C, Chan RH, Crean A, Rakowski H, Rowin EJ, Care M, Deva D, Williams L, Appelbaum E, Gibson CM, Lesser JR, Haas TS, Udelson JE, Manning WJ, Siminovitch K, Ralph-Edwards AC, Rastegar H, Maron BJ, Maron MS.

Eur Heart J. 2014 Oct 14;35(39):2706-13. doi: 10.1093/eurheartj/ehu154. Epub 2014 May 8.

PubMed [citation]

PMID:: 24810389

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059121.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	11	not provided	not provided	clinical testing	PubMed (3)

Description

The p.Glu728X variant in MYBPC3 has been identified in 3 individuals with HCM an d segregated with disease in 3 affected relatives (LMM data). It was absent from large population databases. This nonsense variant leads to a premature terminat ion codon at position 728, which is predicted to lead to a truncated or absent p rotein. Heterozygous loss of function of the MYBPC3 gene is an established disea se mechanism in HCM. In summary, this variant meets our criteria to be classifie d as pathogenic based on predicted impact on the protein, absence from controls, case observations, and segregation in affected family members. ACMG/AMP Criteri a applied: PVS1, PM2, PP1, PS4_Supporting.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		11	not provided	4	not provided

From Center for Human Genetics, University of Leuven, SCV000886757.1

#	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	not provided	not provided	not provided		not provided	not provided	2	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001417126.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Glu728*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42605). 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

Last Updated: Sep 29, 2024

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