Submissions for variant NM_019892.6(INPP5E):c.1133G>A (p.Arg378His)

gnomAD frequency: 0.00002  dbSNP: rs758951947

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV001074128	SCV001239697	likely pathogenic	Retinal dystrophy	2019-01-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001862537	SCV002196775	pathogenic	Familial aplasia of the vermis	2022-11-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 378 of the INPP5E protein (p.Arg378His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of inherited retinal dystrophy (PMID: 29186038; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 866268). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on INPP5E protein function. This variant disrupts the p.Arg378 amino acid residue in INPP5E. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15786477, 19668216). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002240581	SCV002511850	uncertain significance	not specified	2023-08-04	criteria provided, single submitter	clinical testing	Variant summary: INPP5E c.1133G>A (p.Arg378His) results in a non-conservative amino acid change located in the Inositol polyphosphate-related phosphatase domain (IPR000300) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.1e-05 in 237470 control chromosomes. c.1133G>A has been reported in the literature in individuals affected with Joubert Syndrome And Related Disorders (Porto_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Additionally, another missense variant in the same residue (c.1132C>T; p.Arg378Cys) has been classifed as pathogenic in our lab, supporting the functional importance of this residue of the protein. The following publication have been ascertained in the context of this evaluation (PMID: 29186038). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
GeneDx	RCV004590089	SCV005079083	uncertain significance	not provided	2023-06-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 23386033, 29186038)
Fulgent Genetics, Fulgent Genetics	RCV005047291	SCV005679987	likely pathogenic	MORM syndrome; Joubert syndrome 1	2024-03-12	criteria provided, single submitter	clinical testing