ClinVar Miner

Submissions for variant NM_024334.2(TMEM43):c.1061G>C (p.Cys354Ser) (rs187262922)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000243510 SCV000318059 uncertain significance Cardiovascular phenotype 2012-12-10 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV000864384 SCV001005178 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 5 2019-12-31 criteria provided, single submitter clinical testing
Color RCV001191115 SCV001358811 likely benign Cardiomyopathy 2019-05-02 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223930 SCV000280492 uncertain significance not specified 2012-12-11 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Cys354Ser (p.C354S, c.1061G>C) in TMEM43 The variant is novel. It has not been reported in association with disease, though it has been seen in a general population sample (reviewed below). In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging; analysis with SIFT predicts it to be tolerated. The cysteine at codon 354 is completely conserved across species. A nearby variant, p.Ser358Leu, was the first TMEM43 variant associated with inherited cardiac disease (Merner et al 2008). It was identified several kindreds in Newfoundland, Canada with a particularly severe form of arrhythmogenic right ventricular cardiomyopathy (ARVC). The variant was found in all 83 affected individuals across 15 families that were presumed to share a common ancestor based on haplotype analysis and origin from a regional genetic isolate. The same group recently reported on the natural history and phenotype of this cohort (Hodgkinson et al 2012). Penetrance was higher and earlier in males than females. The phenotype was characterized by early death, heart failure, and at least one family meeting diagnostic criteria for ARVC. Nearly half (43%) of affected individuals had left ventricular enlargement fulfilling criteria for dilated cardiomyopathy. With respect Mr. Givens's personal and family history, 10% of carriers had left ventricular hypertrophy, however this was not statistically significantly different from the 6% of non-carriers who had left ventricular hypertrophy. They did not report non-compaction or significant conduction system disease as part of the phenotype. TMEM43 encodes transmembrane protein 43 and is thought to play a role in maintaining nuclear envelope structure by organizing protein complexes at the inner nuclear membrane. To date ARVC is the only condition that TMEM43 has been linked to with strong evidence. Investigators have looked for TMEM43 variants in patiens with other types of cardiomyopathy in some cases rare variants have been found, but to date the evidence for these being causative is weak (Liang et al 2011- TMEM43 in Emery-Dreifuss muscular dystrophy, Haywood et al 2009 ASHG annual meeting - rare variants found in DCM co-occuring with pathogenic variants in LMNA and DMD). In total the variant has not been seen in 1 of ~7294 individuals in publicly available population datasets. There is no variation at codon 354 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6200 Caucasian and African American individuals (as of December 12th, 2012). There is rare variant listed in this dataset in nearby codons (p.Pro343Leu, p.Glu342Asp, p.Thr366Ala, p.Phe369Leu). Per the Ambry report, the variant was observed in 1/1094 individuals studies. Specifically, it was found in 1/93 Finnish individuals.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.