ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.1208A>T (p.Asp403Val)

gnomAD frequency: 0.00004  dbSNP: rs913030626
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV001075397 SCV001241019 uncertain significance Retinal dystrophy 2018-07-18 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001206811 SCV001378140 pathogenic not provided 2024-10-12 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 403 of the ABCA4 protein (p.Asp403Val). This variant is present in population databases (no rsID available, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of Stargardt disease and/or Stargardt disease (PMID: 25066811; internal data). ClinVar contains an entry for this variant (Variation ID: 866970). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCA4 protein function. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001206811 SCV002097557 uncertain significance not provided 2022-02-08 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: 25066811)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV005056863 SCV005726912 uncertain significance not specified 2024-11-08 criteria provided, single submitter clinical testing Variant summary: ABCA4 c.1208A>T (p.Asp403Val) results in a non-conservative amino acid change in 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 4e-06 in 251466 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1208A>T has been reported in the literature in individuals affected with Retinitis Pigmentosa without detailed clinical presentation of these individuals (Zernant_2014, Hanany_2020, Cornelis_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Retinitis Pigmentosa. 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: 35120629, 31964843, 25066811). ClinVar contains an entry for this variant (Variation ID: 866970). Based on the evidence outlined above, the variant was classified as uncertain significance.

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