ClinVar Miner

Submissions for variant NM_024334.2(TMEM43):c.1150C>G (p.Leu384Val) (rs193922706)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000030552 SCV000053223 uncertain significance not specified 2019-01-16 criteria provided, single submitter clinical testing Variant summary: TMEM43 c.1150C>G (p.Leu384Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.4e-05 in 277150 control chromosomes (gnomAD). The observed variant frequency is approximately 6.49 fold of the estimated maximal expected allele frequency for a pathogenic variant in TMEM43 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (8.3e-06), strongly suggesting that the variant is benign. c.1150C>G has been reported in the literature in an individual affected with dilated cardiomyopathy (Forleo_2017). This report does not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Invitae RCV000699323 SCV000828029 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 5 2018-06-15 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 384 of the TMEM43 protein (p.Leu384Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs193922706, ExAC 0.02%). This variant has not been reported in the literature in individuals with TMEM43-related disease. ClinVar contains an entry for this variant (Variation ID: 36870). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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