Submissions for variant NM_024334.3(TMEM43):c.344T>C (p.Leu115Pro)

gnomAD frequency: 0.00001  dbSNP: rs376182664

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183953	SCV000236446	uncertain significance	not provided	2024-08-01	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 37745463)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001069329	SCV001234489	uncertain significance	Arrhythmogenic right ventricular dysplasia 5	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 115 of the TMEM43 protein (p.Leu115Pro). This variant is present in population databases (rs376182664, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with TMEM43-related conditions. ClinVar contains an entry for this variant (Variation ID: 202129). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TMEM43 protein function with a positive predictive value of 80%. 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.
Color Diagnostics, LLC DBA Color Health	RCV001181146	SCV001346240	uncertain significance	Cardiomyopathy	2023-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 115 of the TMEM43 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/251296 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002453668	SCV002616207	uncertain significance	Cardiovascular phenotype	2019-05-20	criteria provided, single submitter	clinical testing	The p.L115P variant (also known as c.344T>C), located in coding exon 4 of the TMEM43 gene, results from a T to C substitution at nucleotide position 344. The leucine at codon 115 is replaced by proline, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV001069329	SCV004841495	uncertain significance	Arrhythmogenic right ventricular dysplasia 5	2024-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 115 of the TMEM43 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/251296 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.