Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000039374 | SCV000063058 | uncertain significance | not specified | 2013-01-13 | criteria provided, single submitter | clinical testing | The 1000+5G>T variant in TMEM43 has not been reported in the literature, but has been identified by our laboratory in 1 individual with HCM, who also carried an other variant likely to be disease-causing (LMM unpublished data). In addition, this variant has been identified in 1/4406 African American chromosomes from a b road population by the NHLBI Exome Sequencing Project (http://evs.gs.washington. edu/EVS/). This variant is located in the 5' splice region. Computational tools suggest a possible impact to splicing, though this information is not predictive enough to determine pathogenicity. Additional information is needed to fully as sess the clinical significance of the 1000+5G>T variant. |
| Invitae | RCV001319828 | SCV001510588 | uncertain significance | Arrhythmogenic right ventricular dysplasia 5 | 2021-03-23 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 11 of the TMEM43 gene. It does not directly change the encoded amino acid sequence of the TMEM43 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs376589026, ExAC 0.01%). This variant has not been reported in the literature in individuals with TMEM43-related conditions. ClinVar contains an entry for this variant (Variation ID: 46137). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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. |
| Fulgent Genetics, |
RCV002483005 | SCV002793197 | uncertain significance | Arrhythmogenic right ventricular dysplasia 5; Emery-Dreifuss muscular dystrophy 7, autosomal dominant; Auditory neuropathy, autosomal dominant 3 | 2021-10-26 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000039374 | SCV004039206 | uncertain significance | not specified | 2023-08-23 | criteria provided, single submitter | clinical testing | Variant summary: TMEM43 c.1000+5G>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 5' splicing donor site and two predict the variant weakens the same canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251322 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1000+5G>T in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters have assessed the variant since 2014, both submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |