Submissions for variant NM_019892.6(INPP5E):c.875G>A (p.Arg292His)

gnomAD frequency: 0.00027  dbSNP: rs199873582

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000194920	SCV000247609	uncertain significance	not specified	2015-02-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001044083	SCV001207858	pathogenic	Familial aplasia of the vermis	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 292 of the INPP5E protein (p.Arg292His). This variant is present in population databases (rs199873582, gnomAD 0.07%). This missense change has been observed in individuals with INPP5E-related conditions (internal data). ClinVar contains an entry for this variant (Variation ID: 211185). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on INPP5E protein function. This variant disrupts the p.Arg292 amino acid residue in INPP5E. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28559085; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV001166425	SCV001328802	uncertain significance	Joubert syndrome 1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000194920	SCV002103941	uncertain significance	not specified	2024-03-14	criteria provided, single submitter	clinical testing	Variant summary: INPP5E c.875G>A (p.Arg292His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 245666 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in INPP5E causing Joubert Syndrome And Related Disorders (0.00028 vs 0.00079), allowing no conclusion about variant significance. c.875G>A has been reported in a heterozygous individual diagnosed with ataxia (Sun_2019). This report does not provide unequivocal conclusions about association of the variant with Joubert Syndrome And Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29915382). ClinVar contains an entry for this variant (Variation ID: 211185). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002517084	SCV003701624	uncertain significance	Inborn genetic diseases	2022-01-05	criteria provided, single submitter	clinical testing	The c.875G>A (p.R292H) alteration is located in exon 2 (coding exon 2) of the INPP5E gene. This alteration results from a G to A substitution at nucleotide position 875, causing the arginine (R) at amino acid position 292 to be replaced by a histidine (H). The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV005042414	SCV005679999	uncertain significance	MORM syndrome; Joubert syndrome 1	2024-06-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528981	SCV004112213	uncertain significance	INPP5E-related disorder	2024-07-09	no assertion criteria provided	clinical testing	The INPP5E c.875G>A variant is predicted to result in the amino acid substitution p.Arg292His. This variant was reported in the heterozygous state in a patient with ataxia and molar tooth sign with additional clinical features (Patient 036 in Sun et al. 2019. PubMed ID: 29915382). However, a second variant was not reported in this patient, and further evidence was not provided to support pathogenicity. A different variant affecting the same amino acid  (p.Arg292Gly)  along with a second variant in this gene was reported to be associated with autosomal recessive retinal disease (Table S4, Stone et al. 2017. PubMed ID: 28559085). The c.875G>A (p.Arg292His) variant is reported in 0.071% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.