ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.5578C>T (p.Arg1860Trp)

gnomAD frequency: 0.00001  dbSNP: rs200849015
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001682640 SCV001905524 likely pathogenic not provided 2021-09-15 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001682640 SCV003523383 pathogenic not provided 2024-10-05 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1860 of the ABCA4 protein (p.Arg1860Trp). This variant is present in population databases (rs200849015, gnomAD 0.006%). This missense change has been observed in individual(s) with retinopathy (PMID: 23982839, 28559085; 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: 1275763). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004587194 SCV005077352 pathogenic Stargardt disease 2024-04-05 criteria provided, single submitter clinical testing Variant summary: ABCA4 c.5578C>T (p.Arg1860Trp) results in a non-conservative amino acid change located in the ABC-2 type transporter, transmembrane domain (IPR013525) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251236 control chromosomes. c.5578C>T has been reported in the literature in multiple individuals affected with Stargardt Disease and related disorders (Fujinami_2013, Khan_2020, Weisschuh_2024, Stone_2017). 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: 32307445, 28559085, 37734845, 23982839). ClinVar contains an entry for this variant (Variation ID: 1275763). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV005023215 SCV005661327 likely pathogenic Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19 2024-04-11 criteria provided, single submitter clinical testing
GeneDx RCV001682640 SCV005848783 likely pathogenic not provided 2024-08-12 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31964843, 29925512, 32307445, 35120629, 23982839, 28559085, 37734845, 38219857)

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