NM_000256.3(MYBPC3):c.1224-52G>A AND Hypertrophic cardiomyopathy

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 17, 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:: RCV001089608.12

Allele description [Variation Report for NM_000256.3(MYBPC3):c.1224-52G>A]

NM_000256.3(MYBPC3):c.1224-52G>A

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.1224-52G>A

HGVS:

NC_000011.10:g.47343314C>T
NG_007667.1:g.14389G>A
NM_000256.3:c.1224-52G>AMANE SELECT
LRG_386t1:c.1224-52G>A
LRG_386:g.14389G>A
NC_000011.9:g.47364865C>T

Links:

dbSNP: rs786204336

NCBI 1000 Genomes Browser:

rs786204336

Molecular consequence:

NM_000256.3:c.1224-52G>A - intron variant - [Sequence Ontology: SO:0001627]

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
SCV001245082	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 11, 2018)	germline	research	PubMed (2) [See all records that cite these PMIDs] 30025578, 25741868
SCV001579888	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 17, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 32396390, 30025578, 32163302, 28492532
SCV001652955	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 18, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30025578, 32163302, 25741868
SCV004812352	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 5, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 30025578, 32163302, 32396390, 33657327, 36980931, 25741868

Help

Summary from all submissions

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

Citations

PubMed

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

Whole Genome Sequencing Improves Outcomes of Genetic Testing in Patients With Hypertrophic Cardiomyopathy.

Bagnall RD, Ingles J, Dinger ME, Cowley MJ, Ross SB, Minoche AE, Lal S, Turner C, Colley A, Rajagopalan S, Berman Y, Ronan A, Fatkin D, Semsarian C.

J Am Coll Cardiol. 2018 Jul 24;72(4):419-429. doi: 10.1016/j.jacc.2018.04.078.

PubMed [citation]

PMID:: 30025578

See all PubMed Citations (7)

Details of each submission

From Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, SCV001245082.1

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

Description

MYBPC3 c.1224-52G>A has been identified previously by another laboratory in a control sample (Genetics Diagnostic Laboratory, CHEO, ClinVar:SCV000219698.2). We identified this variant in two HCM probands, and for one family it was found to segregate to one first-degree family member (Bagnall et al., 2018). This variant is present at a low frequency in the Genome Aggregation Database (MAF=0.00003; http://gnomad.broadinstitute.org/), and is absent in Bravo (http://bravo.sph.umich.edu). Splice prediction tools SpliceSiteFinder, MaxEntScan and NNsplice all predict the variant disrupts splicing. RNA studies showed that this variant results in the creation of a new acceptor site which causes an additional 50 base pairs to be spliced in with exon 14, this would cause a shift in the reading frame downstream and consequently a premature stop codon (Bagnall RD et al., 2018). Based on the adapted ACMG guidelines (Kelly et al., 2018), RNA studies show this variant results altered splicing (PS3), the variant is rare in the general population (PM2), and has been identified in at least 2 HCM probands, therefore we classify MYBPC3 c.12224-52G>A as 'likely pathogenic'.

#	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	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001579888.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change falls in intron 13 of the MYBPC3 gene. It does not directly change the encoded amino acid sequence of the MYBPC3 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs786204336, gnomAD 0.01%). This variant has been observed in individuals with hypertrophic cardiomyopathy (PMID: 30025578, 32163302, 32396390). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188544). Studies have shown that this variant results in aberrant splicing and introduces a premature termination codon (PMID: 30025578, 32163302). The resulting mRNA is expected to undergo nonsense-mediated decay. 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, SCV001652955.2

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

Description

The c.1224-52G>A variant in MYBPC3 has been reported in > 30 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in at least 7 affected relatives from 5 families (Bagnall 2018 PMID: 30025578, Harper 2020 PMID: 32163302). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 188544) and has also been identified in 0.003% (2/68000) of European chromosomes and 0.002% (1/41364) of African chromosomes but is absent from all other populations in gnomAD, including the South Asian population (http://gnomad.broadinstitute.org, v.3.1.2). Computational splice prediction tools predict an impact on splicing through the creation of a new donor splice site which was also corroborated by functional studies using patient RNA from blood. These showed that this variant impacted splicing, resulting in the inclusion of 50 additional intronic nucleotides that results in a frameshift that leads to a premature termination codon 30 amino acids downstream (Bagnall 2018 PMID: 30025578, Harper 2020 PMID: 32163302). This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MYBPC3 gene is an established disease mechanism in autosomal HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2_Supporting, PS3_Moderate, PP3.

#	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 Molecular Genetics, Royal Melbourne Hospital, SCV004812352.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change in MYBPC3 is an intronic variant located in intron 13. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.015% (12/78,060 alleles) in the South Asian population. The variant has been identified in ~1% of individuals with hypertrophic cardiomyopathy (HCM), a prevalence that is significantly increased compared with the prevalence in the population (PMID: 32396390). The variant has been reported to segregate with HCM in multiple unrelated families (PMID: 32163302, 32396390). This variant has been observed as homozygous in two siblings with severe infantile cardiomyopathy (PMID: 36980931). The results from an in silico splicing predictor (SpliceAI) indicate that this variant may impact splicing by disrupting the acceptor splice site of intron 13 of MYBPC3. This prediction is confirmed by RT-PCR and RNA sequencing. The assays demonstrated that the variant impacts splicing by apparently near complete cryptic acceptor activation leading to 50 bp intron 13 inclusion and an out-of-frame extension of exon 14 (p.Ser408fs*31; PMID: 30025578, 32163302, 33657327). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1_Strong, PP1_Strong, PS4.

#	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	not provided	not provided

Last Updated: Nov 3, 2024

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