ClinVar Miner

Submissions for variant NM_201253.3(CRB1):c.3686G>C (p.Cys1229Ser)

gnomAD frequency: 0.00001  dbSNP: rs1031415706
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001350386 SCV001544783 pathogenic Retinitis pigmentosa 12; Leber congenital amaurosis 8 2024-04-08 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 1229 of the CRB1 protein (p.Cys1229Ser). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individuals with clinical features of CRB1-related conditions (PMID: 25474345; Invitae). ClinVar contains an entry for this variant (Variation ID: 1045903). 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.
Baylor Genetics RCV003473873 SCV004211152 likely pathogenic Leber congenital amaurosis 8 2023-08-24 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005005862 SCV005637078 likely pathogenic Pigmented paravenous retinochoroidal atrophy; Retinitis pigmentosa 12; Leber congenital amaurosis 8 2024-01-30 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004740672 SCV005346079 uncertain significance CRB1-related disorder 2024-07-26 no assertion criteria provided clinical testing The CRB1 c.3686G>C variant is predicted to result in the amino acid substitution p.Cys1229Ser. This variant has been reported in the compound heterozygous state in an individual with Stargardt macular dystrophy (Zaneveld et al. 2015. PubMed ID: 25474345). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Missense prediction programs classify this amino acid change as damaging; however, no functional studies have been performed to confirm this. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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