NM_000256.3(MYBPC3):c.3226_3227insT (p.Asp1076fs) 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:: RCV000470975.18

Allele description [Variation Report for NM_000256.3(MYBPC3):c.3226_3227insT (p.Asp1076fs)]

NM_000256.3(MYBPC3):c.3226_3227insT (p.Asp1076fs)

Gene:

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

Variant type:

Insertion

Cytogenetic location:

11p11.2

Genomic location:

Preferred name:

NM_000256.3(MYBPC3):c.3226_3227insT (p.Asp1076fs)

HGVS:

NC_000011.10:g.47333297_47333298insA
NG_007667.1:g.24405_24406insT
NM_000256.3:c.3226_3227insTMANE SELECT
NP_000247.2:p.Asp1076fs
LRG_386t1:c.3226_3227insT
LRG_386:g.24405_24406insT
LRG_386p1:p.Asp1076fs
NC_000011.9:g.47354848_47354849insA
c.3226_3227insT
p.Asp1076ValfsX6
p.D1076VfsX6

Protein change:

D1076fs

Links:

dbSNP: rs397516008

NCBI 1000 Genomes Browser:

rs397516008

Molecular consequence:

NM_000256.3:c.3226_3227insT - frameshift variant - [Sequence Ontology: SO:0001589]

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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Chst10 protein, partial [Mus musculus]
Chst10 protein, partial [Mus musculus]
gi|20071288|gb|AAH26960.1|

Protein
Kneria cytochrome c oxidase subunit I (COX1) gene, complete cds; mitochondrial.
Kneria cytochrome c oxidase subunit I (COX1) gene, complete cds; mitochondrial.
PopSet: 1934508593

PopSet
LOC100007645 [Danio rerio]
LOC100007645 [Danio rerio]
Gene ID:100007645

Gene
NEB nebulin [Gallus gallus]
NEB nebulin [Gallus gallus]
Gene ID:374027

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000059217	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Aug 14, 2019)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 24510615, 27532257, 20474083, 25611685, 24793961, 24033266
SCV000546397	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 19, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 19574547, 20474083, 24510615, 25031304, 25611685, 27532257, 28492532
SCV004836639	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 26, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 20474083, 24510615, 25031304, 25611685, 27532257, 31006259, 32841044, 33495596, 33495597, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000059217

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Aug 14, 2019)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV000546397

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 19, 2024)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV004836639

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 26, 2023)

germline

clinical testing

PubMed (10)
[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	19	9	not provided	108544	not provided	clinical testing

Citations

PubMed

Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic cardiomyopathy.

Bos JM, Will ML, Gersh BJ, Kruisselbrink TM, Ommen SR, Ackerman MJ.

Mayo Clin Proc. 2014 Jun;89(6):727-37. doi: 10.1016/j.mayocp.2014.01.025. Epub 2014 May 1.

PubMed [citation]

PMID:: 24793961
PMCID:: PMC4234122

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 (14)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059217.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	18	not provided	not provided	clinical testing	PubMed (6)

Description

The p.Asp1076ValfsX6 variant in MYBPC3 has been reported in >20 individuals with HCM and segregated with disease in 3 affected individuals from 3 families (Bos 2014, Kapplinger 2014, Walsh 2017, LMM data). It has also been identified in 1/15396 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the proteinâ€™s amino acid sequence beginning at position 1076 and leads to a premature termination codon 6 amino acids downstream. 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 dominant HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PVS1, PS4, PM2, PP1.

#	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		18	not provided	9	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000546397.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change creates a premature translational stop signal (p.Asp1076Valfs*6) 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 individuals with cardiomyopathy (PMID: 20474083, 24510615, 25031304, 25611685, 27532257). ClinVar contains an entry for this variant (Variation ID: 42694). 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 All of Us Research Program, National Institutes of Health, SCV004836639.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (10)

Description

This variant inserts 1 nucleotide in exon 30 of the MYBPC3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. An experimental functional study has shown that this variant may cause mislocalization of the MYBPC3 protein within the sarcomere and decreased incorporation into myofilament (DOI:10.1161/circ.130.suppl_2.20311). This variant has been reported in over twenty individuals affected with hypertrophic cardiomyopathy (PMID: 24510615, 25031304, 25611685, 27532257, 31006259, 32841044, 33495596, 33495597). It has also been reported in individuals affected with dilated cardiomyopathy (PMID: 20474083). This variant has been identified in 1/31354 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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