Submissions for variant NM_006096.3(NDRG1):c.1027C>T (p.Arg343Cys) (rs146613168)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Clinical Services Laboratory,Illumina	RCV001095219	SCV000472127	uncertain significance	Charcot-Marie-Tooth disease, type 4D	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000462824	SCV000551847	uncertain significance	Charcot-Marie-Tooth disease type 4	2019-11-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 343 of the NDRG1 protein (p.Arg343Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs146613168, ExAC 0.04%). This variant has not been reported in the literature in individuals with NDRG1-related disease. ClinVar contains an entry for this variant (Variation ID: 362031). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx	RCV000478522	SCV000573221	uncertain significance	not provided	2018-08-01	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the NDRG1 gene. The R343C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R343C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R343C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.