ClinVar Miner

Submissions for variant NM_006096.3(NDRG1):c.122A>G (p.His41Arg) (rs2233318)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000236642 SCV000614151 uncertain significance not specified 2016-10-13 criteria provided, single submitter clinical testing
GeneDx RCV000766501 SCV000292636 uncertain significance not provided 2016-01-05 criteria provided, single submitter clinical testing The H41R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or with any significant frequency in the 1000 Genomes Project. The H41R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, missense mutations in the NDRG1 gene have not been reported in the Human Gene Mutation Database in association with neuropathy (Stenson et al., 2014). However, this substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000551572 SCV000657840 uncertain significance Charcot-Marie-Tooth disease type 4 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 41 of the NDRG1 protein (p.His41Arg). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs2233318, ExAC 0.2%). This variant has not been reported in the literature in individuals with NDRG1-related disease. ClinVar contains an entry for this variant (Variation ID: 245649). 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: "Tolerated"; PolyPhen-2: "Possibly 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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