ClinVar Miner

Submissions for variant NM_024334.3(TMEM43):c.424G>A (p.Glu142Lys) (rs145619906)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000172593 SCV000051424 likely benign not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000039386 SCV000063070 uncertain significance not specified 2015-04-10 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Glu142Lys var iant in TMEM43 has been previously reported in 3 individuals with ARVC/D (Baskin 2013, Haywood 2013) and was identified by our laboratory in 1 Caucasian child w ith congenital DCM. In addition, this variant has been identified in 0.1% (49/66 614) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://e; dbSNP rs145619906) and was also identified in 1 homozygo us reportedly healthy control individual (Haywood 2013). Computational predictio n tools and conservation analysis suggest that this variant may impact the prote in, though this information is not predictive enough to determine pathogenicity. In summary, while the clinical significance of the p.Glu142Lys variant is uncer tain, the frequency of this variant and its presence in an unaffected homozygous control individual suggests that it is more likely to be benign.
GeneDx RCV000039386 SCV000236427 uncertain significance not specified 2017-05-15 criteria provided, single submitter clinical testing The E142K variant has previously been reported in three individuals with ARVC, one of whom harbored another variant in the DSP gene (Baskin et al., 2013, Haywood et al., 2013). However, the E142K variant has also been observed in the homozygous state in one control individual (Haywood et al., 2013), and has been observed in two other individuals referred for exome sequencing for indications unrelated to cardiomyopathy, arrhythmia, or family history of sudden cardiac death (Ng et al., 2013; Maxwell et al., 2016). Additionally, this variant is observed in 49/66614 (0.07%) alleles from individuals of Non-Finnish European ancestry, and in 5/11560 (0.04%) alleles from individuals of Latino ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Nevertheless, E142K is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, while this substitution occurs at a position that is largely conserved across species, lysine (K) is the wild-type residue at this position in at least one mammalian species. Finally, this variant has also been classified in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar SCV000063070.4, SCV000318759.1, SCV000545857.1; Landrum et al., 2016).
Ambry Genetics RCV000250239 SCV000318759 uncertain significance Cardiovascular phenotype 2019-05-03 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV001084741 SCV000545857 likely benign Arrhythmogenic right ventricular cardiomyopathy, type 5 2019-12-31 criteria provided, single submitter clinical testing
Color RCV001188634 SCV001355720 likely benign Cardiomyopathy 2019-11-05 criteria provided, single submitter clinical testing

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