ClinVar Miner

Submissions for variant NM_025114.4(CEP290):c.5777G>A (p.Arg1926Gln)

dbSNP: rs778030031
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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 RCV001880271 SCV002200699 uncertain significance Familial aplasia of the vermis; Meckel-Gruber syndrome; Nephronophthisis 2022-06-14 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1926 of the CEP290 protein (p.Arg1926Gln). This variant is present in population databases (rs778030031, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with CEP290-related conditions. ClinVar contains an entry for this variant (Variation ID: 990683). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg1926 amino acid residue in CEP290. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21153841, 29398085, 31630094, 32865313). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics RCV002504402 SCV002815485 uncertain significance Leber congenital amaurosis 10; Meckel syndrome, type 4; Senior-Loken syndrome 6; Joubert syndrome 5; Bardet-Biedl syndrome 14 2021-12-03 criteria provided, single submitter clinical testing
Natera, Inc. RCV001278750 SCV001465782 uncertain significance Leber congenital amaurosis 2020-04-17 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004733222 SCV005345656 uncertain significance CEP290-related disorder 2024-06-17 no assertion criteria provided clinical testing The CEP290 c.5777G>A variant is predicted to result in the amino acid substitution p.Arg1926Gln. To our knowledge this variant has not been reported in the literature. Another substitution at this amino acid position (p.Arg1926Pro) has been reported in individuals with Leber congenital amaurosis (Sallum et al. 2020. PubMed ID: 32865313; Sheck et al. 2018. PubMed ID: 29398085; Wiszniewski et al. 2010. PubMed ID: 21153841) and has been classified as likely pathogenic or pathogenic by multiple labs in ClinVar (ID: 659046). This variant is reported in 0.0031% of alleles in individuals of Latino descent in gnomAD. Although we suspect this variant may be pathogenic, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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