Submissions for variant NM_001142800.2(EYS):c.3695T>C (p.Ile1232Thr)

gnomAD frequency: 0.00016  dbSNP: rs146413074

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000667080	SCV000791475	uncertain significance	Retinitis pigmentosa 25	2017-05-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001245737	SCV001419042	uncertain significance	not provided	2024-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1232 of the EYS protein (p.Ile1232Thr). This variant is present in population databases (rs146413074, gnomAD 0.04%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 22164218, 29159838). ClinVar contains an entry for this variant (Variation ID: 551910). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt EYS protein function with a negative predictive value of 80%. This variant disrupts the p.Ile232 amino acid residue in EYS. Other variant(s) that disrupt this residue have been observed in individuals with EYS-related conditions (PMID: 20333770), which suggests that this may be a clinically significant amino acid residue. 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.
Fulgent Genetics, Fulgent Genetics	RCV000667080	SCV002777380	uncertain significance	Retinitis pigmentosa 25	2021-09-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003994072	SCV004813798	uncertain significance	not specified	2024-02-20	criteria provided, single submitter	clinical testing	Variant summary: EYS c.3695T>C (p.Ile1232Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.7e-05 in 155446 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in EYS causing Retinitis Pigmentosa (7.7e-05 vs 0.0034), allowing no conclusion about variant significance. c.3695T>C has been reported in the literature in individuals affected with Retinitis Pigmentosa (examples: Gonzlez-del Pozo_2011, Messchaert_2018, Xu_2021). 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. The following publications have been ascertained in the context of this evaluation (PMID: 22164218, 29159838, 34178978). ClinVar contains an entry for this variant (Variation ID: 551910). Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004817876	SCV005072947	uncertain significance	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000667080	SCV002084405	uncertain significance	Retinitis pigmentosa 25	2020-08-31	no assertion criteria provided	clinical testing