Submissions for variant NM_022489.4(INF2):c.3563C>T (p.Ser1188Phe) (rs201715539)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Clinical Services Laboratory,Illumina	RCV000370054	SCV000385308	benign	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV000508357	SCV000604027	uncertain significance	not specified	2016-09-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000508357	SCV000725143	likely benign	not specified	2017-12-01	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000649975	SCV000771812	uncertain significance	Focal segmental glomerulosclerosis 5; Charcot-Marie-Tooth disease, dominant intermediate E	2019-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces serine with phenylalanine at codon 1188 of the INF2 protein (p.Ser1188Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs201715539, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with INF2-related disease. ClinVar contains an entry for this variant (Variation ID: 312711). 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 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.