Submissions for variant NM_022489.4(INF2):c.1264C>T (p.Pro422Ser)

gnomAD frequency: 0.00012  dbSNP: rs767748953

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001067341	SCV001232398	uncertain significance	Focal segmental glomerulosclerosis 5; Charcot-Marie-Tooth disease dominant intermediate E	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 422 of the INF2 protein (p.Pro422Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with pes cavus, length dependent sensory loss, hypoactive reflexes (Invitae). ClinVar contains an entry for this variant (Variation ID: 860938). 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 with a negative predictive value of 95%. 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.
Illumina Laboratory Services, Illumina	RCV001112035	SCV001269652	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.
Ambry Genetics	RCV002445347	SCV002676784	likely benign	Inborn genetic diseases	2021-11-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV003425910	SCV004118060	uncertain significance	INF2-related disorder	2022-12-16	criteria provided, single submitter	clinical testing	The INF2 c.1264C>T variant is predicted to result in the amino acid substitution p.Pro422Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.014% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-105173868-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.