ClinVar Miner

Submissions for variant NM_022489.4(INF2):c.1183G>A (p.Glu395Lys) (rs374769850)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235504 SCV000293038 uncertain significance not provided 2015-08-13 criteria provided, single submitter clinical testing The E395K variant in the INF2 gene has not been published as pathogenic, nor has it been reported as a benign polymorphism to our knowledge. The E395K variant was not observed at any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E395K 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. However, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. We interpret E395K as a variant of unknown significance.
Invitae RCV001243475 SCV001416638 uncertain significance Focal segmental glomerulosclerosis 5; Charcot-Marie-Tooth disease, dominant intermediate E 2019-10-24 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 395 of the INF2 protein (p.Glu395Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with INF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 245865). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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