Submissions for variant NM_022489.4(INF2):c.2709G>C (p.Gln903His)

dbSNP: rs762803590

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001112575	SCV001270246	uncertain significance	Focal segmental glomerulosclerosis 5	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	RCV002558124	SCV002937220	uncertain significance	Focal segmental glomerulosclerosis 5; Charcot-Marie-Tooth disease dominant intermediate E	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 903 of the INF2 protein (p.Gln903His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 30373780). ClinVar contains an entry for this variant (Variation ID: 882696). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt INF2 protein function. 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.
PreventionGenetics, part of Exact Sciences	RCV003405321	SCV004113988	uncertain significance	INF2-related condition	2022-08-26	criteria provided, single submitter	clinical testing	The INF2 c.2709G>C variant is predicted to result in the amino acid substitution p.Gln903His. This variant was reported as a variant of uncertain significance in an individual with Charcot-Marie-Tooth disease, type 2 (Bacquet et al 2018. PubMed ID: 30373780). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.