Submissions for variant NM_201253.3(CRB1):c.3997G>A (p.Glu1333Lys)

gnomAD frequency: 0.00001  dbSNP: rs137853136

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV004527798	SCV000915384	uncertain significance	CRB1-related disorder	2017-10-04	criteria provided, single submitter	clinical testing	The CRB1 c.3997G>A (p.Glu1333Lys) missense variant has been reported in a single study in which i was reported in a compound heterozygous state with a second missense variant in one individual with autosomal recessive retinitis pigmentosa (Ge et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.000027 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the limited evidence, the p.Glu1333Lys variant is classified as a variant of unknown significance but suspicious for pathogenicity for CRB1-related disorders.
Blueprint Genetics	RCV001073728	SCV001239287	uncertain significance	Retinal dystrophy	2017-09-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001201620	SCV001372699	pathogenic	Retinitis pigmentosa 12; Leber congenital amaurosis 8	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1333 of the CRB1 protein (p.Glu1333Lys). This variant is present in population databases (rs137853136, gnomAD 0.003%). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 26667666; Invitae). ClinVar contains an entry for this variant (Variation ID: 632096). 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%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323720	SCV004029978	uncertain significance	not specified	2023-07-07	criteria provided, single submitter	clinical testing	Variant summary: CRB1 c.3997G>A (p.Glu1333Lys) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251414 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3997G>A has been reported in the literature in at least one compound heterozygous individual affected with Retinitis Pigmentosa (example: Ge_2015). 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 publication has been ascertained in the context of this evaluation (PMID: 26667666). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=3) or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV001825517	SCV002090214	uncertain significance	Leber congenital amaurosis	2020-01-15	no assertion criteria provided	clinical testing