ClinVar Miner

Submissions for variant NM_019892.6(INPP5E):c.1388C>T (p.Ala463Val)

gnomAD frequency: 0.00006  dbSNP: rs199956627
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001338742 SCV001532434 uncertain significance Familial aplasia of the vermis 2023-11-27 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 463 of the INPP5E protein (p.Ala463Val). This variant is present in population databases (rs199956627, gnomAD 0.04%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 28454995). This variant is also known as p.Ala464Val. ClinVar contains an entry for this variant (Variation ID: 800892). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001844251 SCV002103942 uncertain significance not specified 2022-02-24 criteria provided, single submitter clinical testing Variant summary: INPP5E c.1388C>T (p.Ala463Val) results in a non-conservative amino acid change located in the Inositol polyphosphate-related phosphatase (IPR000300) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.4e-05 in 248302 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in INPP5E causing Joubert Syndrome And Related Disorders (6.4e-05 vs 0.00079), allowing no conclusion about variant significance. c.1388C>T has been reported in the literature in a homozygous individual diagnosed with Joubert syndrome 1 & periventricular heterotopia (Alfares_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic (n=1) and as uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Ambry Genetics RCV002549635 SCV003581942 uncertain significance Inborn genetic diseases 2022-06-03 criteria provided, single submitter clinical testing Occurs in the first base pair of the exon Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences RCV004536010 SCV004114905 uncertain significance INPP5E-related disorder 2023-07-14 criteria provided, single submitter clinical testing The INPP5E c.1388C>T variant is predicted to result in the amino acid substitution p.Ala463Val. This variant, reported as c.1388C>T p.Ala464Val, was found in the homozygous state in a patient with Joubert syndrome and periventricular heterotopia (Table S2, Alfares et al. 2017. PubMed ID: 28454995). No additional studies were reported to help assess the pathogenicity of this variant. This variant is reported in 0.039% of alleles in individuals of Ashkenazi Jewish descent in gnomAD ( At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City RCV000985083 SCV001133043 likely pathogenic Joubert syndrome 1 2019-09-26 no assertion criteria provided clinical testing

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