Submissions for variant NM_022489.4(INF2):c.395T>C (p.Leu132Pro)

dbSNP: rs387907038

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001380434	SCV001578512	pathogenic	Focal segmental glomerulosclerosis 5; Charcot-Marie-Tooth disease dominant intermediate E	2020-08-08	criteria provided, single submitter	clinical testing	This variant disrupts the p.Leu132 amino acid residue in INF2. Other variant(s) that disrupt this residue have been observed in individuals with INF2-related conditions (PMID: 22187985), which suggests that this may be a clinically significant amino acid residue. 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 expected to disrupt INF2 protein function. This variant has been observed in individual(s) with Charcot-Marie-Tooth disease and focal segmental glomerulosclerosis (PMID: 24750328, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 637706). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 132 of the INF2 protein (p.Leu132Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV002462135	SCV002756702	likely pathogenic	not provided	2022-05-19	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24750328, 22965130)
Ambry Genetics	RCV004027379	SCV004887968	pathogenic	Inborn genetic diseases	2023-11-21	criteria provided, single submitter	clinical testing	The c.395T>C (p.L132P) alteration is located in exon 3 (coding exon 2) of the INF2 gene. This alteration results from a T to C substitution at nucleotide position 395, causing the leucine (L) at amino acid position 132 to be replaced by a proline (P). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported as de novo in an individual with features of Charcot-Marie-Tooth disease and focal segmental glomerulosclerosis (Park, 2014; Park, 2023). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). In multiple assays testing INF2 function, this variant showed functionally abnormal results (Bayraktar, 2020). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Inherited Neuropathy Consortium	RCV000789988	SCV000929377	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only