Submissions for variant NM_019892.6(INPP5E):c.1760del (p.Val587fs)

gnomAD frequency: 0.00002  dbSNP: rs775518991

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UW Hindbrain Malformation Research Program, University of Washington	RCV000201536	SCV000256417	pathogenic	Familial aplasia of the vermis	2015-02-23	criteria provided, single submitter	research
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376306	SCV001573400	likely pathogenic	Rod-cone dystrophy	2021-04-08	criteria provided, single submitter	research	The INPP5E c.1760delT 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: PVS1, PM2. Based on this evidence we have classified this variant as Likely Pathogenic.
Invitae	RCV000201536	SCV002208539	pathogenic	Familial aplasia of the vermis	2022-05-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val587Glyfs*7) in the INPP5E gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 58 amino acid(s) of the INPP5E protein. This variant is present in population databases (rs775518991, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Joubert syndrome and/or retinitis pigmentosa (PMID: 26092869; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 217656). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the INPP5E protein in which other variant(s) (p.Pro597Leu) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003897436	SCV004714857	pathogenic	INPP5E-related condition	2024-02-21	criteria provided, single submitter	clinical testing	The INPP5E c.1760delT variant is predicted to result in a frameshift and premature protein termination (p.Val587Glyfs*7). This variant has been reported in an individual with Joubert syndrome (Table S5, Bachmann-Gagescu et al. 2015. PubMed ID: 26092869) and it has also been reported in an individual with an inherited retinal degeneration (Figure 1, Sangermano et al. 2021. PubMed ID: 34188062). This variant is reported in 0.0033% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in INPP5E are expected to be pathogenic. This variant is interpreted as pathogenic.