Submissions for variant NM_201253.3(CRB1):c.4130G>A (p.Gly1377Glu)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV005222573	SCV005869304	likely pathogenic	Retinitis pigmentosa 12; Leber congenital amaurosis 8	2024-04-03	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1377 of the CRB1 protein (p.Gly1377Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early onset retinal dystrophy (PMID: 31630094). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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%. 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.