ClinVar Miner

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

gnomAD frequency: 0.00027  dbSNP: rs199873582
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Total submissions: 6
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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
Invitae RCV001044083 SCV001207858 pathogenic Familial aplasia of the vermis 2024-01-29 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 (Invitae). ClinVar contains an entry for this variant (Variation ID: 211185). 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) has been performed at Invitae 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; Invitae). 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.
PreventionGenetics, part of Exact Sciences RCV004528981 SCV004112213 uncertain significance INPP5E-related disorder 2024-01-22 criteria provided, single submitter 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.

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