ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.5186T>C (p.Leu1729Pro)

gnomAD frequency: 0.00001  dbSNP: rs61750567
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000085703 SCV001223878 pathogenic not provided 2024-11-27 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1729 of the ABCA4 protein (p.Leu1729Pro). This variant is present in population databases (rs61750567, gnomAD 0.007%). This missense change has been observed in individual(s) with a diagnosis of, or clinical features of, Stargardt disease (PMID: 10206579, 11328725, 25066811, 25082885; internal data). 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: 99350). 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 ABCA4 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001074107 SCV001239676 pathogenic Retinal dystrophy 2019-01-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004689457 SCV005185043 pathogenic Retinitis pigmentosa 2024-05-22 criteria provided, single submitter clinical testing Variant summary: ABCA4 c.5186T>C (p.Leu1729Pro) results in a non-conservative amino acid change located in the ABC-2 type transporter, transmembrane domain (IPR013525) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-06 in 239016 control chromosomes. c.5186T>C has been reported in the literature in multiple individuals affected with macular degeneration, Stargardt dystrophy, STGD1 and Central Vision Loss (example, Alapatizz_2014, Cornelis_2022, Fishman_1999, Webster_2001, Zernant_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25082885, 35120629, 10206579, 11328725, 25066811). ClinVar contains an entry for this variant (Variation ID: 99350). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV005031589 SCV005663297 pathogenic Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19 2024-05-31 criteria provided, single submitter clinical testing
Retina International RCV000085703 SCV000117843 not provided not provided no assertion provided not provided

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