NM_000256.3(MYBPC3):c.2542_2543delinsTG (p.Ala848Trp) AND Hypertrophic cardiomyopathy

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 7, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003586309.1

Allele description [Variation Report for NM_000256.3(MYBPC3):c.2542_2543delinsTG (p.Ala848Trp)]

NM_000256.3(MYBPC3):c.2542_2543delinsTG (p.Ala848Trp)

Gene:

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

Variant type:

Indel

Cytogenetic location:

11p11.2

Genomic location:

Preferred name:

NM_000256.3(MYBPC3):c.2542_2543delinsTG (p.Ala848Trp)

HGVS:

NC_000011.10:g.47337450_47337451delinsCA
NG_007667.1:g.20252_20253delinsTG
NM_000256.3:c.2542_2543delinsTGMANE SELECT
NP_000247.2:p.Ala848Trp
LRG_386t1:c.2542_2543delinsTG
LRG_386:g.20252_20253delinsTG
LRG_386p1:p.Ala848Trp
NC_000011.9:g.47359001_47359002delinsCA
NM_000256.3:c.2542_2543delGCinsTGMANE SELECT

Protein change:

A848W

Links:

dbSNP: rs2142855225

NCBI 1000 Genomes Browser:

rs2142855225

Molecular consequence:

NM_000256.3:c.2542_2543delinsTG - missense variant - [Sequence Ontology: SO:0001583]

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
SCV004300184	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 7, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25740977, 28408708, 28416588, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004300184

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 7, 2023)

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

Citations

PubMed

A founder MYBPC3 mutation results in HCM with a high risk of sudden death after the fourth decade of life.

Calore C, De Bortoli M, Romualdi C, Lorenzon A, Angelini A, Basso C, Thiene G, Iliceto S, Rampazzo A, Melacini P.

J Med Genet. 2015 May;52(5):338-47. doi: 10.1136/jmedgenet-2014-102923. Epub 2015 Mar 4.

PubMed [citation]

PMID:: 25740977

Nonfamilial Hypertrophic Cardiomyopathy: Prevalence, Natural History, and Clinical Implications.

Ingles J, Burns C, Bagnall RD, Lam L, Yeates L, Sarina T, Puranik R, Briffa T, Atherton JJ, Driscoll T, Semsarian C.

Circ Cardiovasc Genet. 2017 Apr;10(2). doi:pii: e001620. 10.1161/CIRCGENETICS.116.001620.

PubMed [citation]

PMID:: 28408708

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV004300184.1

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

Description

This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Ala848 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25740977, 28408708, 28416588; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1308439). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change replaces alanine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 848 of the MYBPC3 protein (p.Ala848Trp).

#	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: May 1, 2024

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