NM_024334.3(TMEM43):c.1150C>G (p.Leu384Val) AND Arrhythmogenic right ventricular dysplasia 5

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 16, 2025
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:: RCV000699323.8

Allele description [Variation Report for NM_024334.3(TMEM43):c.1150C>G (p.Leu384Val)]

NM_024334.3(TMEM43):c.1150C>G (p.Leu384Val)

Gene:

TMEM43:transmembrane protein 43 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p25.1

Genomic location:

Preferred name:

NM_024334.3(TMEM43):c.1150C>G (p.Leu384Val)

HGVS:

NC_000003.12:g.14141742C>G
NG_008975.1:g.21803C>G
NM_024334.3:c.1150C>GMANE SELECT
NP_077310.1:p.Leu384Val
NP_077310.1:p.Leu384Val
LRG_435t1:c.1150C>G
LRG_435:g.21803C>G
LRG_435p1:p.Leu384Val
NC_000003.11:g.14183242C>G
NM_024334.2:c.1150C>G

Protein change:

L384V

Links:

dbSNP: rs193922706

NCBI 1000 Genomes Browser:

rs193922706

Molecular consequence:

NM_024334.3:c.1150C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Arrhythmogenic right ventricular dysplasia 5
Synonyms:: ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 5; Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy 5
Identifiers:: MONDO: MONDO:0011459; MedGen: C1858379; OMIM: 604400

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000828029	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 16, 2025)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28750076, 31760239, 28492532
SCV004841619	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Sep 23, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28750076, 31760239, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000828029

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 16, 2025)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004841619

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Sep 23, 2024)

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	5	not provided	not provided	143475	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

Targeted next-generation sequencing detects novel gene-phenotype associations and expands the mutational spectrum in cardiomyopathies.

Forleo C, D'Erchia AM, Sorrentino S, Manzari C, Chiara M, Iacoviello M, Guaricci AI, De Santis D, Musci RL, La Spada A, Marangelli V, Pesole G, Favale S.

PLoS One. 2017;12(7):e0181842. doi: 10.1371/journal.pone.0181842.

PubMed [citation]

PMID:: 28750076
PMCID:: PMC5531468

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000828029.4

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

Description

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 384 of the TMEM43 protein (p.Leu384Val). This variant is present in population databases (rs193922706, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of TMEM43-related conditions (PMID: 28750076, 31760239; internal data). ClinVar contains an entry for this variant (Variation ID: 36870). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TMEM43 protein function with a negative predictive value of 80%. 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, SCV004841619.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces leucine with valine at codon 384 of the TMEM43 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy who also carried an additional variant in MYBPC3 (PMID: 28750076). It has also been reported in an individual affected with sudden cardiac death who also carried an additional variant in DSP that appeared to segregate with arrhythmogenic left ventricular cardiomyopathy in an affected child (PMID: 31760239). This variant has been identified in 15/282786 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	143475	not provided	not provided		5	not provided	not provided	not provided

Last Updated: May 16, 2025

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