Submissions for variant NM_019892.6(INPP5E):c.1730C>G (p.Pro577Arg)

gnomAD frequency: 0.00405  dbSNP: rs147967974

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001095320	SCV000478747	uncertain significance	Joubert syndrome 1	2018-01-12	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.
GeneDx	RCV000489191	SCV000577458	uncertain significance	not provided	2017-03-29	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the INPP5E gene. The P577R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P577R variant is observed in 25/9198 (0.3%) alleles from individuals of European background, including one homozygous individual (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is not conserved, and Arginine is observed at this position in evolution. However, the P577R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000302693	SCV001000685	benign	Familial aplasia of the vermis	2023-11-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000489191	SCV003917744	benign	not provided	2023-01-01	criteria provided, single submitter	clinical testing	INPP5E: BS1, BS2