Submissions for variant NM_019892.6(INPP5E):c.1630G>A (p.Asp544Asn)

gnomAD frequency: 0.00001  dbSNP: rs1161636527

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001755662	SCV002005260	uncertain significance	not provided	2019-04-11	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV004783983	SCV005397674	likely pathogenic	Joubert syndrome 1	2023-10-09	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (G>A) at position 1630 of the coding sequence of the INPP5E gene that results in an aspartic acid to asparagine amino acid change at residue 544 of the inositol polyphosphate-5-phosphatase E protein. The 544 residue falls in the inositol polyphosphate phosphatase catalytic domain which is critical to inositol polyphosphate-5-phosphatase E's role in stabilizing cilia and phosphatidylinositol signaling (PMID: 19668216). This is a previously reported variant (ClinVar 1319014) that has not been observed in individuals affected by INPP5E-related disorder in the published literature. This variant is present in 2 of 151786 alleles (0.001%) in the gnomAD v3.1.2 population dataset. Multiple bioinformatic tools predict that this aspartic acid to asparagine amino acid change would be damaging, and the Asp544 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been published to our knowledge. Based upon the evidence, we consider this a likely pathogenic variant. ACMG Criteria: PM1, PM2, PM3, PP2, PP3
PreventionGenetics, part of Exact Sciences	RCV004756292	SCV005341597	uncertain significance	INPP5E-related disorder	2024-01-18	no assertion criteria provided	clinical testing	The INPP5E c.1630G>A variant is predicted to result in the amino acid substitution p.Asp544Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0033% of alleles in individuals of South 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.