Submissions for variant NM_019892.6(INPP5E):c.1132C>T (p.Arg378Cys)

dbSNP: rs121918130

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000636941	SCV000758388	pathogenic	Familial aplasia of the vermis	2023-09-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg378 amino acid residue in INPP5E. Other variant(s) that disrupt this residue have been observed in individuals with INPP5E-related conditions (PMID: 29186038), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects INPP5E function (PMID: 19668216). 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 expected to disrupt INPP5E protein function. ClinVar contains an entry for this variant (Variation ID: 400). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 15786477, 19668216). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121918130, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 378 of the INPP5E protein (p.Arg378Cys).
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV000735369	SCV000854522	pathogenic	Clubfoot; Skeletal dysplasia; Micrognathia; Hemivertebrae; Preaxial foot polydactyly; Respiratory failure; Short femur; Vertebral segmentation defect; Pseudoarthrosis; Chronic lung disease; Abnormal pulmonary interstitial morphology; Coat hanger sign of ribs; Vertebral hypoplasia; Absent epiphyses; Cleft palate; Patent ductus arteriosus		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001267543	SCV001445724	likely pathogenic	Inborn genetic diseases	2018-02-28	criteria provided, single submitter	clinical testing
GeneDx	RCV001550720	SCV001771098	likely pathogenic	not provided	2023-03-29	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: inability to block Akt phosphorylation in the presence of PDGF stimulation (Bielas et al., 2009); 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: 19668216, 23022135, 27401686, 23386033, 15786477, 30755392)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265543	SCV002547525	pathogenic	Joubert syndrome and related disorders	2022-05-31	criteria provided, single submitter	clinical testing	Variant summary: INPP5E c.1132C>T (p.Arg378Cys) 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 3.4e-05 in 236434 control chromosomes. c.1132C>T has been reported in the literature in multiple individuals affected with Joubert Syndrome And Related Disorders (example, Bielas_2009, Sangermano_2021, Sheck_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Bielas_2009). The most pronounced variant effect results in approximately 50% of normal 5'-phosphatase activity towards PtdIns(4,5)P2 as substrate corroborated by a zebrafish model (Xu_2017). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003904789	SCV004725077	likely pathogenic	INPP5E-related condition	2024-02-01	criteria provided, single submitter	clinical testing	The INPP5E c.1132C>T variant is predicted to result in the amino acid substitution p.Arg378Cys. This variant has been reported in the homozygous state in two related individuals with Joubert Syndrome; an in vitro enzymatic assay in this same study showed the p.Arg378Cys variant has impaired 5-phosphatase activity compared to wildtype (Bielas et al 2009. PubMed ID: 19668216). This variant has also been reported in an additional individual with retinal disease (Table S1, Karali et al. 2022. PubMed ID: 36460718). This variant is reported in 0.021% of alleles in individuals of African descent in gnomAD. A different substitution of this amino acid (p.Arg378His) has also been reported in the compound heterozygous state in an individual with Leber congenital amaurosis (Porto et al. 2017. PubMed ID: 29186038). Given the evidence, we interpret c.1132C>T (p.Arg378Cys) as likely pathogenic.
OMIM	RCV000022405	SCV000043090	pathogenic	Joubert syndrome 1	2009-09-01	no assertion criteria provided	literature only