NM_000256.3(MYBPC3):c.1792delG AND Hypertrophic cardiomyopathy

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 6, 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:: RCV001065541.8

Allele description [Variation Report for NM_000256.3(MYBPC3):c.1792delG]

NM_000256.3(MYBPC3):c.1792delG

Gene:

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

Variant type:

Deletion

Cytogenetic location:

11p11.2

Genomic location:

Preferred name:

NM_000256.3(MYBPC3):c.1792delG

HGVS:

NC_000011.10:g.47341245del
NG_007667.1:g.16460del
NM_000256.3:c.1792delGMANE SELECT
LRG_386t1:c.1792del
LRG_386:g.16460del
NC_000011.10:g.47341243delC
NC_000011.9:g.47362794del
NC_000011.9:g.47362796del
NM_000256.3:c.1792delMANE SELECT
p.V598SfsX4

Links:

dbSNP: rs730880647

NCBI 1000 Genomes Browser:

rs730880647

Molecular consequence:

NM_000256.3:c.1792delG - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

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

Recent activity

Clear Turn Off Turn On

xl11086B06R_1397356 Xenopus ORFeome version 1.0 library Xenopus laevis cDNA clon...
xl11086B06R_1397356 Xenopus ORFeome version 1.0 library Xenopus laevis cDNA clone xl11086B06 3', mRNA sequence
gi|798033553|gnl|dbEST|79655538|gb| 836.1|

Nucleotide

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001230501	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 6, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19574547, 28492532
SCV004848081	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 15, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28087566, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001230501

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 6, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004848081

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 15, 2017)

germline

clinical testing

PubMed (2)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency.

Marston S, Copeland O, Jacques A, Livesey K, Tsang V, McKenna WJ, Jalilzadeh S, Carballo S, Redwood C, Watkins H.

Circ Res. 2009 Jul 31;105(3):219-22. doi: 10.1161/CIRCRESAHA.109.202440. Epub 2009 Jul 2.

PubMed [citation]

PMID:: 19574547

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001230501.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change creates a premature translational stop signal (p.Val598Serfs*4) 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 variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 181074). 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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848081.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.Val598fs variant in MYBPC3 has not been previously reported in the literature, but has been reported in ClinVar (Variation ID 181074). It was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 598 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in HCM. In summary, the p.Val598fs variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon its predicted impact to the protein and absence from controls.

#	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

ClinVar

Relating variation to medicine