Submissions for variant NM_022489.4(INF2):c.3103G>A (p.Gly1035Ser) (rs368995122)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000421859	SCV000529456	likely benign	not specified	2017-02-09	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	RCV000525037	SCV000652102	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 glycine with serine at codon 1035 of the INF2 protein (p.Gly1035Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs368995122, ExAC 0.04%), 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: 387417). 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 serine 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757410	SCV000885619	uncertain significance	not provided	2018-01-12	criteria provided, single submitter	clinical testing	The INF2 c.3103G>A; p.Gly1035Ser variant (rs368995122), to our knowledge, is not reported in the medical literature nor has it been previously identified by our laboratory. It is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.03% in the non-Finnish European population (identified in 33 out of 110,380 chromosomes), and is classified as likely benign/unknown significance in ClinVar (Variant ID: 387417). The glycine at position 1035 is weakly conserved, considering 12 species, and computational analyses of the effects of the p.Gly1035Ser variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, MutationTaster: polymorphism, PolyPhen-2: benign). Based on the available information, the clinical significance of the p.Gly1035Ser variant cannot be determined with certainty.
Illumina Clinical Services Laboratory,Illumina	RCV001113918	SCV001271731	benign	Focal segmental glomerulosclerosis 5	2018-01-12	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.