Submissions for variant NM_001142800.2(EYS):c.6415T>C (p.Cys2139Arg)

dbSNP: rs1378663182

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001377570	SCV001574938	likely pathogenic	not provided	2022-03-20	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Cys2139 amino acid residue in EYS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20333770, 25356976, 25753737). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1066550). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 25366773; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 2139 of the EYS protein (p.Cys2139Arg).
Baylor Genetics	RCV003462951	SCV004195290	likely pathogenic	Retinitis pigmentosa 25	2023-05-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004801001	SCV005422239	likely pathogenic	Retinitis pigmentosa	2024-10-22	criteria provided, single submitter	clinical testing	Variant summary: EYS c.6415T>C (p.Cys2139Arg) results in a non-conservative amino acid change located in the EGF like domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 152386 control chromosomes. c.6415T>C has been reported in the literature in individuals affected with Retinitis Pigmentosa (examples: Pierrottet_2014, Colombo_2021, Internal data). These data indicate that the variant may be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.6416G>A, p.Cys2139Tyr), supporting the critical relevance of codon 2139 to EYS protein function. 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: 33576794,25366773, NO_PMID).ClinVar contains an entry for this variant (Variation ID: 1066550). Based on the evidence outlined above, the variant was classified as likely pathogenic.