ClinVar Miner

Submissions for variant NM_201253.3(CRB1):c.3961T>G (p.Cys1321Gly)

dbSNP: rs62635649
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mendelics RCV000986497 SCV001135509 likely pathogenic Leber congenital amaurosis 1 2019-05-28 criteria provided, single submitter clinical testing
3billion RCV001809876 SCV002058544 likely pathogenic Retinitis pigmentosa 12 2022-01-03 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported to be associated with CRB1 related disorder (ClinVar ID: VCV000801602, PMID:33576794). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 15024725, PM3_M). A different missense change at the same codon has been reported to be associated with CRB1 related disorder (ClinVar ID: VCV000099904, PMID:15024725,26667666, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.943, 3CNET: 0.781, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics RCV002489456 SCV002801488 likely pathogenic Pigmented paravenous retinochoroidal atrophy; Retinitis pigmentosa 12; Leber congenital amaurosis 8 2021-12-17 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003455005 SCV004180211 likely pathogenic Leber congenital amaurosis 8 2023-04-11 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003455006 SCV004180212 likely pathogenic Pigmented paravenous retinochoroidal atrophy 2023-04-11 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001809876 SCV004180213 likely pathogenic Retinitis pigmentosa 12 2023-04-11 criteria provided, single submitter clinical testing
Baylor Genetics RCV003455005 SCV004211131 likely pathogenic Leber congenital amaurosis 8 2024-01-25 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003769294 SCV004577370 likely pathogenic Retinitis pigmentosa 12; Leber congenital amaurosis 8 2023-09-17 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 1321 of the CRB1 protein (p.Cys1321Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with CRB1-related conditions (PMID: 15024725, 31725702, 33576794). ClinVar contains an entry for this variant (Variation ID: 801602). 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. This variant disrupts the p.Cys1321 amino acid residue in CRB1. Other variant(s) that disrupt this residue have been observed in individuals with CRB1-related conditions (PMID: 26667666), which suggests that this may be a clinically significant amino acid residue. 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.

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