Submissions for variant NM_022489.4(INF2):c.383T>C (p.Leu128Pro)

dbSNP: rs387907037

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235466	SCV000293539	likely pathogenic	not provided	2017-05-12	criteria provided, single submitter	clinical testing	The L128P variant has been previously reported in association with CMT and focal segmental glomerulosclerosis (Rodriguez et al., 2013; Boyer et al., 2011). It was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L128P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution alters a conserved position in the DID domain, where other pathogenic variants associated with CMT-FSGS have been reported (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001378421	SCV001575985	pathogenic	Focal segmental glomerulosclerosis 5; Charcot-Marie-Tooth disease dominant intermediate E	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 128 of the INF2 protein (p.Leu128Pro). 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 and focal segmental glomerulosclerosis (PMID: 22187985, 22961558). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 30867). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002362594	SCV002626032	pathogenic	Inborn genetic diseases	2020-06-17	criteria provided, single submitter	clinical testing	The p.L128P variant (also known as c.383T>C), located in coding exon 1 of the INF2 gene, results from a T to C substitution at nucleotide position 383. The leucine at codon 128 is replaced by proline, an amino acid with similar properties. This alteration is located in the diaphanous inhibitory domain (DID), where pathogenic alterations are localized between nucleotide positions 300 to 500 in patients with both Charcot-Marie-Tooth disease, intermediate E (CMTDIE) and focal segmental glomerulosclerosis 5 (FSGS) (Boyer O et al. N. Engl. J. Med., 2011 Dec;365:2377-88). This variant has been found in multiple individuals with CMT and FSGS and was reported as de novo in one individual (Boyer O et al. N. Engl. J. Med., 2011 Dec;365:2377-88; Rodriguez PQ et al. Pediatr. Nephrol., 2013 Feb;28:339-43). The variant has also been reported in one individual with an unspecified inherited neuropathy phenotype (Laššuthová P et al. Orphanet J Rare Dis, 2016 08;11:118). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
OMIM	RCV000023852	SCV000045143	pathogenic	Charcot-Marie-Tooth disease dominant intermediate E	2011-12-22	no assertion criteria provided	literature only