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

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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.
Illumina Clinical Services Laboratory,Illumina	RCV000462824	SCV000472127	uncertain significance	Charcot-Marie-Tooth disease type 4	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000462824	SCV000551847	uncertain significance	Charcot-Marie-Tooth disease type 4	2018-12-19	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.

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