Submissions for variant NM_019892.6(INPP5E):c.1325C>T (p.Thr442Ile)

gnomAD frequency: 0.00006  dbSNP: rs201043370

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001095351	SCV000478757	uncertain significance	Joubert syndrome 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000383155	SCV001210558	uncertain significance	Familial aplasia of the vermis	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 442 of the INPP5E protein (p.Thr442Ile). This variant is present in population databases (rs201043370, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with INPP5E-related conditions. ClinVar contains an entry for this variant (Variation ID: 365885). 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 not expected to disrupt INPP5E 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.
Ambry Genetics	RCV002523760	SCV003689574	uncertain significance	Inborn genetic diseases	2022-12-21	criteria provided, single submitter	clinical testing	The c.1325C>T (p.T442I) alteration is located in exon 6 (coding exon 6) of the INPP5E gene. This alteration results from a C to T substitution at nucleotide position 1325, causing the threonine (T) at amino acid position 442 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV003231468	SCV003929745	uncertain significance	not provided	2023-06-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23386033)
PreventionGenetics, part of Exact Sciences	RCV003932516	SCV004753357	uncertain significance	INPP5E-related condition	2023-11-03	criteria provided, single submitter	clinical testing	The INPP5E c.1325C>T variant is predicted to result in the amino acid substitution p.Thr442Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-139326993-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.