NM_000256.3(MYBPC3):c.26-2A>G AND multiple conditions

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Sep 16, 2022
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:: RCV002496530.6

Allele description [Variation Report for NM_000256.3(MYBPC3):c.26-2A>G]

NM_000256.3(MYBPC3):c.26-2A>G

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.26-2A>G

HGVS:

NC_000011.10:g.47351507T>C
NG_007667.1:g.6196A>G
NG_122461.1:g.262T>C
NM_000256.3:c.26-2A>GMANE SELECT
LRG_386t1:c.26-2A>G
LRG_386:g.6196A>G
NC_000011.9:g.47373058T>C
c.26-2A>G

Links:

dbSNP: rs376395543

NCBI 1000 Genomes Browser:

rs376395543

Molecular consequence:

NM_000256.3:c.26-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

Observations:

Condition(s)

Name:: Hypertrophic cardiomyopathy 4
Synonyms:: Familial hypertrophic cardiomyopathy 4
Identifiers:: MONDO: MONDO:0007268; MedGen: C1861862; OMIM: 115197

Name:: Left ventricular noncompaction 10 (LVNC10)
Identifiers:: MONDO: MONDO:0014163; MedGen: C3715165; Orphanet: 154; Orphanet: 54260; OMIM: 615396

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002808696	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 4, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003920227	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003925325	New York Genome Center	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Pathogenic (Sep 16, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002808696

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 4, 2022)

unknown

clinical testing

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

SCV003920227

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 30, 2021)

germline

clinical testing

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

SCV003925325

New York Genome Center

criteria provided, single submitter

(NYGC Assertion Criteria 2020)

Pathogenic
(Sep 16, 2022)

germline

clinical testing

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Fulgent Genetics, Fulgent Genetics, SCV002808696.1

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

From Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, SCV003920227.1

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

Description

MYBPC3 NM_000256.3 exon 2 c.26-2A>G: This variant has been reported in the literature in several individuals with HCM or LVNC, segregating with disease in multiple affected family members within at least two families (Van Driest 2004 PMID:15519027, Ehlermann 2008 PMID:18957093, Page 2012 PMID:22267749, Sedaghat-Hamedani 2017 PMID:29029073, Walsh 2017 PMID:27532257). This variant is present in 0.005% (6/115748) of European alleles in the Genome Aggregation Database http://gnomad.broadinstitute.org/variant/11-47373058-T-C). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, reduced penetrance, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:42644). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant alters the consensus splice sequence (+/- 1,2) which is predicted to result in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Marston 2009 PMID:19574547). In summary, this variant is classified as pathogenic based on the data above (segregation studies, impact to protein etc.)

#	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 New York Genome Center, SCV003925325.1

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

Description

The c.26-2A>G variant identified in the MYBPC3 gene has been reported in ClinVar as Pathogenic by multiple submitters (VarID:42644) and has been reported in several individuals affected with hypertrophic cardiomyopathy in the literature [PMID: 15519027, 18957093, 27532257, 33673806,others.] The c.26-2A>G variant is observed in 10 alleles (~0.002% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2,TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.26-2A>G variant in MYBPC3 is located inthe canonical splice acceptor site preceding exon 2 of this 34-exon gene, and is presumed to affect mRNA splicing which might result in exon skipping or full/partial intron retention. Based on available evidence this c.26-2A>G variant identified in MYBPC3 is classified as Pathogenic.

#	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: Nov 24, 2024

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