Submissions for variant NM_201253.3(CRB1):c.3653G>A (p.Cys1218Tyr)

dbSNP: rs1450635782

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000986496	SCV001135508	likely pathogenic	Leber congenital amaurosis 1	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001726405	SCV001961153	likely pathogenic	not provided	2022-08-01	criteria provided, single submitter	clinical testing	CRB1: PM2, PM3, PM5
DASA	RCV001824163	SCV002073769	likely pathogenic	Retinitis pigmentosa 12	2022-02-05	criteria provided, single submitter	clinical testing	The c.3653G>A;p.(Cys1218Tyr) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 801601) - PS4_supporting. This variant is not present in population databases (rs1450635782; gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (Clinvar ID: 866855 - c.3653G>T;p.Cys1218Phe; PMID: 15459956; 12700176) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic.
Invitae	RCV001858644	SCV002279230	pathogenic	Retinitis pigmentosa 12; Leber congenital amaurosis 8	2023-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1218 of the CRB1 protein (p.Cys1218Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with CRB1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 801601). 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) performed at Invitae indicates that this missense variant is expected to disrupt CRB1 protein function with a positive predictive value of 95%. This variant disrupts the p.Cys1218 amino acid residue in CRB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12700176; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331014	SCV004039023	uncertain significance	not specified	2023-08-10	criteria provided, single submitter	clinical testing	Variant summary: CRB1 c.3653G>A (p.Cys1218Tyr) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) 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 249062 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3653G>A in individuals affected with Retinal Dystrophy and no experimental evidence demonstrating its impact on protein function have been reported. However, a different missense variant at this codon has been previously classified as pathogenic/disease causing (HGMD:CM034731, ClinVar:866855), suggesting this residue may of clinical significance. Four ClinVar submitters have assessed the variant since 2014: three classified the variant as likely pathogenic and one as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.