NM_000256.3(MYBPC3):c.26-2A>G AND Hypertrophic cardiomyopathy 4

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Nov 7, 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:: RCV000656561.13

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000778606	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - AGHI-GT-HudsonAlpha	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 8, 2018)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV001366311	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 1, 2016)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001429300	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 29, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004045794	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Nov 7, 2022)	paternal	clinical testing	Citation Link,
SCV005043327	Clinical Genomics Laboratory, Stanford Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 29, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing
not provided	paternal	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	1	not provided	not provided	1	not provided	research

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 HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - AGHI-GT-HudsonAlpha, SCV000778606.1

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

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

From Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001366311.2

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

Description

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PP3.

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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001429300.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	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		2	not provided	not provided	not provided

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV004045794.1

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

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

From Clinical Genomics Laboratory, Stanford Medicine, SCV005043327.1

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

Description

The c.26-2A>G variant in the MYBPC3gene has been previously reported in many unrelated individuals with hypertrophic cardiomyopathy(Van Driest et al., 2004; Ehlermann et al., 2008; Kapplinger et al., 2014; Walsh et al., 2017), and segregated in 6 affected relatives from a five-generation family with left ventricular non-compaction (Sedaghat-Hamedani et al., 2017). This variant has been identified in6/115,748 European non-Finnish chromosomes(7/255,378 chromosomesoverall)by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with the prevalence of hypertrophic cardiomyopathy.The c.26-2A>G variant alters the canonical acceptor splice site in intron 1, which is predicted to result in abnormal gene splicing.Heterozygous loss-of-function is an established mechanism of disease for the MYBPC3gene(Helms et al., 2020).These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the c.26-2A>G variant as pathogenic for autosomal dominant hypertrophic cardiomyopathy based on the information above. [ACMG evidence codes used: PVS1_Strong; PS4; PM2; PP1]

#	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		1	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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