Submissions for variant NM_006096.3(NDRG1):c.660C>A (p.Asn220Lys) (rs143549909)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000488995	SCV000576995	uncertain significance	not provided	2018-08-22	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the NDRG1 gene. The N220K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is observed in 40/10152 (0.4%) alleles from individuals of Ashkenazi Jewish background in large population cohorts as well as 1 homozygous individual undergoing testing at GeneDx (Lek et al., 2016). The N220K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000654148	SCV000776038	uncertain significance	Charcot-Marie-Tooth disease type 4	2017-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine with lysine at codon 220 of the NDRG1 protein (p.Asn220Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is present in population databases (rs143549909, ExAC 0.02%). This variant has not been reported in the literature in individuals with NDRG1-related disease. ClinVar contains an entry for this variant (Variation ID: 426529). 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: "Benign"; Align-GVGD: "Class C65"). 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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