Submissions for variant NM_019892.6(INPP5E):c.1402C>T (p.Arg468Cys)

gnomAD frequency: 0.00002  dbSNP: rs375909217

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV001074129	SCV001239698	uncertain significance	Retinal dystrophy	2019-01-16	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198896	SCV001369891	uncertain significance	Joubert syndrome 1	2020-04-01	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3.
Invitae	RCV001320437	SCV001511221	likely pathogenic	Familial aplasia of the vermis	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 468 of the INPP5E protein (p.Arg468Cys). This variant is present in population databases (rs375909217, gnomAD 0.006%). This missense change has been observed in individuals with INPP5E-related conditions (PMID: 34188062; Invitae). ClinVar contains an entry for this variant (Variation ID: 866269). 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 INPP5E protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376361	SCV001573478	uncertain significance	Rod-cone dystrophy	2021-04-08	criteria provided, single submitter	research	The INPP5E c.1402C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
GeneDx	RCV003329377	SCV004036945	likely pathogenic	not provided	2023-09-23	criteria provided, single submitter	clinical testing	Observed with a likely pathogenic variant in siblings with juvenile-onset rod cone degeneration in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Sangermano et al., 2021); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23386033, 34188062)
PreventionGenetics, part of Exact Sciences	RCV004528376	SCV004108571	uncertain significance	INPP5E-related disorder	2024-01-23	criteria provided, single submitter	clinical testing	The INPP5E c.1402C>T variant is predicted to result in the amino acid substitution p.Arg468Cys. This variant was reported in an individual with retinal degeneration (Sangermano et al. 2021. PubMed ID: 34188062, supplementary data). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.