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

gnomAD frequency: 0.00006  dbSNP: rs199956627

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	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.
Breakthrough Genomics, Breakthrough Genomics	RCV004693420	SCV005190586	uncertain significance	not provided		criteria provided, single submitter	not provided
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000985083	SCV005441845	uncertain significance	Joubert syndrome 1	2024-12-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005047157	SCV005680296	uncertain significance	MORM syndrome; Joubert syndrome 1	2024-03-21	criteria provided, single submitter	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000985083	SCV001133043	likely pathogenic	Joubert syndrome 1	2019-09-26	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004536010	SCV004114905	uncertain significance	INPP5E-related disorder	2024-07-09	no assertion criteria provided	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). It has also been described as heterozygous in an individual with Joubert syndrome but who had a diagnostic finding in KIF7 (Table S5, Phelps et al. 2018. PubMed ID: 28771248). 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.