Submissions for variant NM_201253.3(CRB1):c.584G>T (p.Cys195Phe)

gnomAD frequency: 0.00005  dbSNP: rs764256655

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255600	SCV000321522	likely pathogenic	not provided	2018-04-03	criteria provided, single submitter	clinical testing	The C195F variant in the CRB1 gene has been reported previously in association with autosomal recessive CRB1-related disorder, in affected individuals who were compound heterozygous for the C195F variant and another pathogenic variant (den Hollander et al., 2004; Morarji et al., 2016). The C195F variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The C195F variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret C195F as a likely pathogenic variant.
Molecular Medicine, University of Leeds	RCV000656138	SCV000611557	pathogenic	Macular dystrophy	2017-10-27	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001040337	SCV001203902	pathogenic	Retinitis pigmentosa 12; Leber congenital amaurosis 8	2024-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 195 of the CRB1 protein (p.Cys195Phe). This variant is present in population databases (rs764256655, gnomAD 0.004%). This missense change has been observed in individual(s) with CRB1-related disease (PMID: 15459956, 26914788, 27096895, 29391521). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 265083). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Blueprint Genetics	RCV001075823	SCV001241459	pathogenic	Retinal dystrophy	2019-07-25	criteria provided, single submitter	clinical testing
Genomics England Pilot Project, Genomics England	RCV001542640	SCV001759997	pathogenic	Retinitis pigmentosa 12		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000255600	SCV002023390	likely pathogenic	not provided	2023-06-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002500956	SCV002812545	pathogenic	Pigmented paravenous retinochoroidal atrophy; Retinitis pigmentosa 12; Leber congenital amaurosis 8	2021-08-26	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003454773	SCV004178830	likely pathogenic	Leber congenital amaurosis 8	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003454774	SCV004178831	likely pathogenic	Pigmented paravenous retinochoroidal atrophy	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001542640	SCV004178832	likely pathogenic	Retinitis pigmentosa 12	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003454773	SCV004211106	pathogenic	Leber congenital amaurosis 8	2024-03-20	criteria provided, single submitter	clinical testing