Submissions for variant NM_001142800.2(EYS):c.1871C>T (p.Ser624Leu)

gnomAD frequency: 0.00001  dbSNP: rs548565748

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779519	SCV000916163	uncertain significance	Retinitis pigmentosa	2018-10-25	criteria provided, single submitter	clinical testing	The EYS c.1871C>T (Ser624Leu) variant is a missense variant that has been reported in one study and is found in a homozygous state in two siblings affected with retinitis pigmentosa (Di et al. 2016). The father was an unaffected heterozygous carrier. No additional family members were available for DNA testing. The p.Ser624Leu variant was not found in homozygous or compound heterozygous state in 1000 controls and is reported at a frequency of 0.000832 in the South Asian population of the Genome Aggregation Database. The evidence for this variant is limited. The p.Ser624Leu variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for autosomal recessive retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV001053114	SCV001217358	uncertain significance	not provided	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 624 of the EYS protein (p.Ser624Leu). This variant is present in population databases (rs548565748, gnomAD 0.08%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 26787102). ClinVar contains an entry for this variant (Variation ID: 632494). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298769	SCV002598698	uncertain significance	not specified	2022-09-26	criteria provided, single submitter	clinical testing	Variant summary: EYS c.1871C>T (p.Ser624Leu) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of 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 0.00018 in 157330 control chromosomes, predominantly at a frequency of 0.00083 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in EYS causing Retinitis Pigmentosa (0.00018 vs 0.0034), allowing no conclusion about variant significance. c.1871C>T has been reported in the literature as a homozygous genotype in two siblings affected with Retinitis Pigmentosa (e.g. Di_2016). The unaffected father was confirmed as a heterozygous carrier however no other family members were available for genetic analysis. This report does not provide unequivocal conclusions about association of the variant with Retinitis Pigmentosa. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000779519	SCV001463557	uncertain significance	Retinitis pigmentosa	2020-09-16	no assertion criteria provided	clinical testing