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NM_024334.3(TMEM43):c.1073C>T (p.Ser358Leu) AND Arrhythmogenic right ventricular dysplasia 5

Germline classification:
Pathogenic (5 submissions)
Last evaluated:
Jan 17, 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:
RCV000000770.17

Allele description

NM_024334.3(TMEM43):c.1073C>T (p.Ser358Leu)

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.1073C>T (p.Ser358Leu)
Other names:
p.S358L:TCG>TTG
HGVS:
  • NC_000003.12:g.14141665C>T
  • NG_008975.1:g.21726C>T
  • NM_024334.3:c.1073C>TMANE SELECT
  • NP_077310.1:p.Ser358Leu
  • NP_077310.1:p.Ser358Leu
  • LRG_435t1:c.1073C>T
  • LRG_435:g.21726C>T
  • LRG_435p1:p.Ser358Leu
  • NC_000003.11:g.14183165C>T
  • NM_024334.2:c.1073C>T
  • Q9BTV4:p.Ser358Leu
  • c.1073C>T
  • p.S358L
Protein change:
S358L; SER358LEU
Links:
UniProtKB: Q9BTV4#VAR_044438; OMIM: 612048.0001; dbSNP: rs63750743
NCBI 1000 Genomes Browser:
rs63750743
Molecular consequence:
  • NM_024334.3:c.1073C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000020920OMIM
no assertion criteria provided
Pathogenic
(Nov 1, 2013)
germlineliterature only

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

SCV000764088Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Dec 7, 2023)
germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV000992155Heart Center, Academic Medical Center Amsterdam
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Dec 1, 2018)
unknownresearch

PubMed (1)
[See all records that cite this PMID]

SCV001983380GeneReviews
no classification provided
not providedgermlineliterature only

PubMed (4)
[See all records that cite these PMIDs]

SCV004363566KardioGenetik, Herz- und Diabeteszentrum NRW
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jan 17, 2024)
maternalclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedunknownyesnot providednot providednot providednot providednot providedresearch
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, literature only
not providedmaternalunknown1not providednot providednot providednot providedclinical testing

Citations

PubMed

The natural history of a genetic subtype of arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43.

Hodgkinson KA, Connors SP, Merner N, Haywood A, Young TL, McKenna WJ, Gallagher B, Curtis F, Bassett AS, Parfrey PS.

Clin Genet. 2013 Apr;83(4):321-31. doi: 10.1111/j.1399-0004.2012.01919.x. Epub 2012 Aug 13.

PubMed [citation]
PMID:
22725725

Exercise testing in asymptomatic gene carriers exposes a latent electrical substrate of arrhythmogenic right ventricular cardiomyopathy.

Perrin MJ, Angaran P, Laksman Z, Zhang H, Porepa LF, Rutberg J, James C, Krahn AD, Judge DP, Calkins H, Gollob MH.

J Am Coll Cardiol. 2013 Nov 5;62(19):1772-9. doi: 10.1016/j.jacc.2013.04.084. Epub 2013 Jun 27.

PubMed [citation]
PMID:
23810883
See all PubMed Citations (9)

Details of each submission

From OMIM, SCV000020920.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (3)

Description

In affected individuals with arrhythmogenic right ventricular dysplasia (ARVD5; 604400) from 15 unrelated Newfoundland families, Merner et al. (2008) identified heterozygosity for a 1073C-T transition in the TMEM43 gene, resulting in a ser358-to-leu (S358L) substitution at a highly conserved residue within the third predicted transmembrane domain. The mutation was not found in 47 spouses or 161 controls. Of 61 'unaffected' individuals who carried the mutation, 35 (57%) were found to have clinical signs of ARVD on subsequent testing, and penetrance was 100% in mutation-positive males and females at ages 63 and 76 years, respectively.

In a Danish woman and her affected mother with ARVD, Christensen et al. (2011) identified heterozygosity for the S358L mutation in the TMEM43 gene. The mutation was not found in the proband's unaffected sister or in 650 ethnically matched controls. The proband became symptomatic at 49 years of age and was diagnosed based on the presence of ventricular tachycardia (VT), T-wave inversion in leads V1 to V5, late potentials on signal-averaged ECG, dilated right ventricle, and fibrofatty infiltrations on endomyocardial biopsy. Her mother, who was subsequently diagnosed at 70 years of age, had similar findings except that biopsy showed fatty infiltrations but no fibrosis. Both patients had normal left ventricular diameter and function. Immunostaining of patient myocardium for TMEM43 showed localization to the sarcolemma, with reduced signal in the patients compared to controls; similar immunostaining for plakoglobin (JUP; 173325) also showed reduced signal, suggesting that TMEM43-associated ARVD shares a final common pathway with desmosome-associated ARVD.

Baskin et al. (2013) identified the TMEM43 S358L 'Newfoundland' mutation in 6 patients, including a 43-year-old New Zealand man who was not of Newfoundland descent. The mutation, which occurred de novo in the New Zealand patient, arose on a different haplotype from that of the patients from Newfoundland, suggesting that S358 might represent a hotspot for sequence alteration.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000764088.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 358 of the TMEM43 protein (p.Ser358Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 18313022, 21214875, 22725725, 23810883, 23812740, 24598986). In at least one individual the variant was observed to be de novo. It is commonly reported in individuals of Newfoundland ancestry (PMID: 18313022, 21214875, 22725725, 23810883, 23812740, 24598986). ClinVar contains an entry for this variant (Variation ID: 734). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TMEM43 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects TMEM43 function (PMID: 25343256). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Heart Center, Academic Medical Center Amsterdam, SCV000992155.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

From GeneReviews, SCV001983380.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From KardioGenetik, Herz- und Diabeteszentrum NRW, SCV004363566.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1maternalunknownnot providednot providednot provided1not providednot providednot provided

Last Updated: Apr 15, 2024