Submissions for variant NM_001142800.2(EYS):c.9344T>A (p.Val3115Asp)

gnomAD frequency: 0.00002  dbSNP: rs748838955

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001227263	SCV001399615	likely pathogenic	not provided	2023-05-27	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. 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 EYS protein function. ClinVar contains an entry for this variant (Variation ID: 636032). This missense change has been observed in individuals with clinical features of inherited retinal dystrophy (PMID: 30718709, 32037395; Invitae). This variant is present in population databases (rs748838955, gnomAD 0.001%). This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 3115 of the EYS protein (p.Val3115Asp).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000787603	SCV003929189	likely pathogenic	Retinitis pigmentosa	2023-04-25	criteria provided, single submitter	clinical testing	Variant summary: EYS c.9344T>A (p.Val3115Asp) results in a non-conservative amino acid change located in the Laminin G domain (IPR001791) 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 6.5e-06 in 153108 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9344T>A has been reported in the literature in both compound heterozygous and homozygous individuals affected with Inherited Retinal Disease (e.g., Jespersgaard_2019, Zampaglione_2020). These data indicate that the variant is likely to be associated with disease. 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: 30718709, 32037395). Four ClinVar submitters (evaluation after 2014) have classified the variant as likely pathogenic (n = 1) or uncertain significance (n = 3). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV001830678	SCV004195266	likely pathogenic	Retinitis pigmentosa 25	2024-03-04	criteria provided, single submitter	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787603	SCV000926586	uncertain significance	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Natera, Inc.	RCV001830678	SCV002083452	uncertain significance	Retinitis pigmentosa 25	2020-09-02	no assertion criteria provided	clinical testing