Submissions for variant NM_024334.3(TMEM43):c.970A>G (p.Asn324Asp)

dbSNP: rs1365389365

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001188842	SCV001355987	uncertain significance	Cardiomyopathy	2020-03-20	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 324 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 cardiovascular disorders in the literature. This variant has been identified in 1/251462 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.
Invitae	RCV001338113	SCV001531753	uncertain significance	Arrhythmogenic right ventricular dysplasia 5	2020-01-23	criteria provided, single submitter	clinical testing	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. 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. This variant has not been reported in the literature in individuals with TMEM43-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with aspartic acid at codon 324 of the TMEM43 protein (p.Asn324Asp). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and aspartic acid.
Ambry Genetics	RCV002379725	SCV002695213	uncertain significance	Cardiovascular phenotype	2020-03-04	criteria provided, single submitter	clinical testing	The p.N324D variant (also known as c.970A>G), located in coding exon 11 of the TMEM43 gene, results from an A to G substitution at nucleotide position 970. The asparagine at codon 324 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003396797	SCV004104603	uncertain significance	TMEM43-related condition	2022-08-24	criteria provided, single submitter	clinical testing	The TMEM43 c.970A>G variant is predicted to result in the amino acid substitution p.Asn324Asp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-14180767-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.