Submissions for variant NM_019892.6(INPP5E):c.746C>T (p.Ser249Phe)

gnomAD frequency: 0.00005  dbSNP: rs550485638

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376540	SCV001573767	likely pathogenic	Rod-cone dystrophy	2021-04-08	criteria provided, single submitter	research	The INPP5E c.746C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM1, PM2, PP3, PM3. Based on this evidence we have classified this variant as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001871993	SCV002180425	uncertain significance	Familial aplasia of the vermis	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 249 of the INPP5E protein (p.Ser249Phe). This variant is present in population databases (rs550485638, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of INPP5E-related conditions (PMID: 27353947, 32483926). ClinVar contains an entry for this variant (Variation ID: 1065823). 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. 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	RCV002550959	SCV003548961	uncertain significance	Inborn genetic diseases	2022-02-09	criteria provided, single submitter	clinical testing	The c.746C>T (p.S249F) alteration is located in exon 1 (coding exon 1) of the INPP5E gene. This alteration results from a C to T substitution at nucleotide position 746, causing the serine (S) at amino acid position 249 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003147627	SCV003835121	uncertain significance	Joubert syndrome 1	2022-01-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226465	SCV003923139	uncertain significance	not specified	2023-03-21	criteria provided, single submitter	clinical testing	Variant summary: INPP5E c.746C>T (p.Ser249Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.3e-05 in 206804 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in INPP5E causing Joubert Syndrome And Related Disorders (7.3e-05 vs 0.00079), allowing no conclusion about variant significance. c.746C>T has been reported in the literature in individuals affected with Joubert Syndrome Related Disorders. These reports do not provide unequivocal conclusions about association of the variant with Joubert Syndrome And Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely pathogenic n=1, VUS n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004815503	SCV005068969	uncertain significance	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV004697127	SCV005198476	uncertain significance	not provided	2023-10-12	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005040233	SCV005680009	uncertain significance	MORM syndrome; Joubert syndrome 1	2024-01-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004756227	SCV005344582	uncertain significance	INPP5E-related disorder	2024-09-24	no assertion criteria provided	clinical testing	The INPP5E c.746C>T variant is predicted to result in the amino acid substitution p.Ser249Phe. This variant has been reported as a variant of uncertain significance in a study of inherited retinal disorders (Table S12 in Diñeiro et al. 2020. PubMed ID: 32483926). This variant was also reported in the homozygous or compound heterozygous state, as part of a complex allele p.[(Ser249Phe); (Arg596Thr)], in two unrelated families with rod cone degeneration (Families F and G, Sangermano et al. 2021. PubMed ID: 34188062). This variant is reported in 0.032% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from likely pathogenic to uncertain (http://www.ncbi.nlm.nih.gov/clinvar/variation/1065823). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.