Submissions for variant NM_024334.3(TMEM43):c.310C>G (p.Pro104Ala)

gnomAD frequency: 0.00004  dbSNP: rs775872602

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001181203	SCV001346303	uncertain significance	Cardiomyopathy	2023-03-29	criteria provided, single submitter	clinical testing	This missense variant replaces proline with alanine at codon 104 of the TMEM43 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TMEM43-related disorders in the literature. This variant has been identified in 11/251210 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001300621	SCV001489767	uncertain significance	Arrhythmogenic right ventricular dysplasia 5	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 104 of the TMEM43 protein (p.Pro104Ala). This variant is present in population databases (rs775872602, gnomAD 0.03%). 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: 921649). 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 not expected to disrupt TMEM43 protein function with a negative 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.
Ambry Genetics	RCV002320402	SCV002607832	likely benign	Cardiovascular phenotype	2022-09-12	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
All of Us Research Program, National Institutes of Health	RCV001300621	SCV004841489	uncertain significance	Arrhythmogenic right ventricular dysplasia 5	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces proline with alanine at codon 104 of the TMEM43 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant 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 11/251210 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.
Clinical Genomics Laboratory, Stanford Medicine	RCV001300621	SCV005684995	uncertain significance	Arrhythmogenic right ventricular dysplasia 5	2023-08-29	criteria provided, single submitter	clinical testing	The p.Pro104Ala variant in the TMEM43 gene has not been previously reported in association with disease. This variant has been identified in 11/34,558 Latino/Admixed American chromosomes (11/251,210 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This allele frequency is higher than expected for a pathogenic variant. This variant is present in ClinVar (Variation ID: 921649). The proline at position 104 is evolutionarily conserved. Computational tools predict that the p.Pro104Ala variant is neither deleterious nor benign; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Pro104Ala variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: BS1_Supporting]