NM_000256.3(MYBPC3):c.1166A>T (p.Asp389Val) AND Hypertrophic cardiomyopathy

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 23, 2023
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:: RCV002560896.4

Allele description [Variation Report for NM_000256.3(MYBPC3):c.1166A>T (p.Asp389Val)]

NM_000256.3(MYBPC3):c.1166A>T (p.Asp389Val)

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.1166A>T (p.Asp389Val)

HGVS:

NC_000011.10:g.47343549T>A
NG_007667.1:g.14154A>T
NM_000256.3:c.1166A>TMANE SELECT
NP_000247.2:p.Asp389Val
LRG_386t1:c.1166A>T
LRG_386:g.14154A>T
LRG_386p1:p.Asp389Val
NC_000011.9:g.47365100T>A
NC_000011.9:g.47365100T>A

Protein change:

D389V

Links:

dbSNP: rs1412710023

NCBI 1000 Genomes Browser:

rs1412710023

Molecular consequence:

NM_000256.3:c.1166A>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hypertrophic cardiomyopathy
Synonyms:: HYPERTROPHIC MYOCARDIOPATHY
Identifiers:: MONDO: MONDO:0005045; MeSH: D002312; MedGen: C0007194; Human Phenotype Ontology: HP:0001639

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003461157	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 26, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29641836, 28492532
SCV004834663	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Aug 23, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29641836, 34769381, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003461157

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 26, 2021)

germline

clinical testing

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

SCV004834663

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Aug 23, 2023)

germline

clinical testing

PubMed (3)
[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	2	not provided	not provided	108544	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

Association of Cardiomyopathy With MYBPC3 D389V and MYBPC3Δ25bpIntronic Deletion in South Asian Descendants.

Viswanathan SK, Puckelwartz MJ, Mehta A, Ramachandra CJA, Jagadeesan A, Fritsche-Danielson R, Bhat RV, Wong P, Kandoi S, Schwanekamp JA, Kuffel G, Pesce LL, Zilliox MJ, Durai UNB, Verma RS, Molokie RE, Suresh DP, Khoury PR, Thomas A, Sanagala T, Tang HC, Becker RC, et al.

JAMA Cardiol. 2018 Jun 1;3(6):481-488. doi: 10.1001/jamacardio.2018.0618.

PubMed [citation]

PMID:: 29641836
PMCID:: PMC6054452

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003461157.1

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

Description

This sequence change replaces aspartic acid with valine at codon 389 of the MYBPC3 protein (p.Asp389Val). The aspartic acid residue is weakly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 29641836). ClinVar contains an entry for this variant (Variation ID: 925145). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.

#	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, SCV004834663.1

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

Description

This missense variant replaces aspartic acid with valine at codon 389 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant presents in tandem on the same allele as the likely benign MYBPC3 variant c.3628-41_3628-17del25 (MYBPC3del25bp). One functional study in wild boar tissue showed that this variant may lead to faster destabilization of sarcomere function than MYBPC3del25bp alone (PMID: 34769381). This variant has not been reported in individuals affected with MYBPC3-related disorders in the literature. Echocardiographic findings from a study screening US South Asian individuals have indicated that left ventricular ejection fraction and left ventricular fractional shortening were significantly increased in the Asp389Val carriers compared to non-carriers, consistent with a hyperdynamic state described in early hypertrophic cardiomyopathy (PMID: 29641836). At a cellular level, cardiomyocytes derived from induced pluripotent stem cells from Asp389Val carriers were significantly more hypertrophic and showed increased frequency of arrhythmic cells as well as ectopic Ca2+ transients compared with control cells (PMID: 29641836). This variant has been identified in 1/244882 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine