NM_000256.3(MYBPC3):c.3124_3125insAA (p.Thr1042fs) AND Hypertrophic cardiomyopathy

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 4, 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:: RCV000697578.11

Allele description

NM_000256.3(MYBPC3):c.3124_3125insAA (p.Thr1042fs)

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.3124_3125insAA (p.Thr1042fs)

HGVS:

NC_000011.10:g.47333623_47333624insTT
NG_007667.1:g.24080_24081insAA
NM_000256.3:c.3124_3125insAAMANE SELECT
NP_000247.2:p.Thr1042fs
LRG_386t1:c.3124_3125insAA
LRG_386:g.24080_24081insAA
LRG_386p1:p.Thr1042fs
NC_000011.9:g.47355173_47355174insTT
NC_000011.9:g.47355174_47355175insTT
p.Thr1042LysfsX5

Protein change:

T1042fs

Links:

dbSNP: rs1064793202

NCBI 1000 Genomes Browser:

rs1064793202

Molecular consequence:

NM_000256.3:c.3124_3125insAA - 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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CR737490 Soares_testis_NHT Homo sapiens cDNA clone IMAGp998D194499; IMAGE:183933...
CR737490 Soares_testis_NHT Homo sapiens cDNA clone IMAGp998D194499; IMAGE:1839330 5', mRNA sequence
gi|51586758|gnl|dbEST|25215382|emb| 490.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000712151	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (May 18, 2016)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9562578, 24033266
SCV000826198	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 4, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9562578, 26914223, 19574547, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000712151

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(May 18, 2016)

germline

clinical testing

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

SCV000826198

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 4, 2022)

germline

clinical testing

PubMed (4)
[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	not provided	3	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy.

Niimura H, Bachinski LL, Sangwatanaroj S, Watkins H, Chudley AE, McKenna W, Kristinsson A, Roberts R, Sole M, Maron BJ, Seidman JG, Seidman CE.

N Engl J Med. 1998 Apr 30;338(18):1248-57.

PubMed [citation]

PMID:: 9562578

See all PubMed Citations (5)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000712151.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (2)

Description

The p.Thr1042fs variant in MYBPC3 has been reported in 1 individual with HCM and segregated with disease in 5 affected relatives (Niimura 1998). It was absent f rom large population studies, though the ability of these studies to accurately detect indels may be limited. This variant is predicted to cause a frameshift, w hich alters the protein?s amino acid sequence beginning at position 1042 and lea ds to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss-of-f unction variants are strongly associated with HCM. In summary, this variant meet s criteria to be classified as pathogenic for HCM in an autosomal dominant manne r based upon segregation studies and predicted impact of the variant.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		3	not provided	1	not provided

From Invitae, SCV000826198.7

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

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 418356). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (HCM) (PMID: 9562578, 26914223). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr1042Lysfs*5) 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).

#	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: Aug 4, 2024

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