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NM_024334.3(TMEM43):c.1073C>T (p.Ser358Leu) AND Familial isolated arrhythmogenic right ventricular dysplasia

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 25, 2016
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:
RCV000588763.2

Allele description [Variation Report for NM_024334.3(TMEM43):c.1073C>T (p.Ser358Leu)]

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]

Condition(s)

Name:
Familial isolated arrhythmogenic right ventricular dysplasia
Identifiers:
MONDO: MONDO:0016342; MedGen: C4274968; OMIM: PS107970

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000699486Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Pathogenic
(Jul 25, 2016)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Perceived economic burden associated with an inherited cardiac condition: a qualitative inquiry with families affected by arrhythmogenic right ventricular cardiomyopathy.

Etchegary H, Enright G, Audas R, Pullman D, Young TL, Hodgkinson K.

Genet Med. 2016 Jun;18(6):584-92. doi: 10.1038/gim.2015.132. Epub 2015 Oct 29.

PubMed [citation]
PMID:
26513349

Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene.

Merner ND, Hodgkinson KA, Haywood AF, Connors S, French VM, Drenckhahn JD, Kupprion C, Ramadanova K, Thierfelder L, McKenna W, Gallagher B, Morris-Larkin L, Bassett AS, Parfrey PS, Young TL.

Am J Hum Genet. 2008 Apr;82(4):809-21. doi: 10.1016/j.ajhg.2008.01.010. Epub 2008 Feb 28.

PubMed [citation]
PMID:
18313022
PMCID:
PMC2427209
See all PubMed Citations (7)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000699486.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

Variant summary: The TMEM43 c.1073C>T (p.Ser358Leu) variant involves the alteration of a conserved nucleotide and is located in third transmembrane domain of the protein (Christensen_2011). 4/4 in silico tools predict a damaging outcome for this variant. Functional studies have shown that the S358L mutant reduces conduction velocity, increases the stiffness cell nuclei and alters the gap junction function (Siragam_PLoS One_2014 and Milting_Eur Heart J_2015). This variant was absent in 123942 control chromosomes. This variant has been widely reported as a founder mutation in Newfoundland. From a study of 15 families from Newfoundland, median age to develop an ARVD associated phenotype was 32 years for males and 44 years for females, with 100% of males and females penetrant by 63 and 76 years, respectively (Milting_Eur Heart J_2015). Haplotype analysis revealed an estimated age of 13001500 years for the mutation, which proves the European origin of the Newfoundland mutation (Milting_Eur Heart J_2015). Interestingly, this variant was also found as a confirmed de novo variant in an ARVC patient from New Zealand. Haplotype analysis revealed that the mutation occurred on a different haplotype in the patient than in the patients from Newfoundland (Baskin_HG_2013). Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.

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

Last Updated: May 12, 2024