ClinVar Miner

Submissions for variant NM_019892.6(INPP5E):c.1862G>A (p.Arg621Gln)

gnomAD frequency: 0.00001  dbSNP: rs1588830568
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ocular Genomics Institute, Massachusetts Eye and Ear RCV001376300 SCV001573394 likely pathogenic Rod-cone dystrophy 2021-04-08 criteria provided, single submitter research The INPP5E c.1862G>A 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, PM3, PM5, PP1. Based on this evidence we have classified this variant as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002282421 SCV002571972 pathogenic Joubert syndrome and related disorders 2022-08-11 criteria provided, single submitter clinical testing Variant summary: INPP5E c.1862G>A (p.Arg621Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251460 control chromosomes (gnomAD). c.1862G>A has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Joubert Syndrome And Related Disorders and with inherited retinal disorders (e.g. Travaglini_2013, Tsurusaki_2013, Fleming_2017, Porto_2017, Sangermano_2021). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV002549199 SCV003021111 pathogenic Familial aplasia of the vermis 2023-10-03 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 621 of the INPP5E protein (p.Arg621Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Joubert syndrome and/or retinitis pigmentosa (PMID: 23034536, 28559085, 29146704, 29186038, 31456290, 34188062). 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: 812336). 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. For these reasons, this variant has been classified as Pathogenic.
Sharon lab, Hadassah-Hebrew University Medical Center RCV001003058 SCV001161115 likely pathogenic Leber congenital amaurosis 2019-06-23 no assertion criteria provided research

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