ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.5381C>A (p.Ala1794Asp) (rs61751406)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mendelics RCV000677343 SCV001135332 pathogenic Stargardt disease 1 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV000085725 SCV001222426 pathogenic not provided 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 1794 of the ABCA4 protein (p.Ala1794Asp). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is present in population databases (rs61751406, ExAC 0.004%). This variant has been observed in individual(s) with ABCA4-related retinal diseases (PMID:29555955, 30093795, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99371, 236131). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Ala1794 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29847635, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV000504739 SCV001239245 pathogenic Retinal dystrophy 2019-08-16 criteria provided, single submitter clinical testing
Retina International RCV000085725 SCV000117865 not provided not provided no assertion provided not provided
Human Molecular Genetics Laboratory,Federal University of Parana RCV000677343 SCV000598613 likely pathogenic Stargardt disease 1 2017-01-12 no assertion criteria provided research We suggest likely pathogenic clinical significance based on the following rationale: - Multiple lines of computational evidence support a deleterious effect (ACMG/AMP guidelines: PP3) - Co-segregation with disease in multiple affected family members (ACMG/AMP guidelines: PP1) - Almost absent in population databases (ACMG/AMP guidelines: PM2; absent from 1000genomes, 3/121412 in EXaC) - Literature data also show that this allele is present in Stargardt patients' ABCA4 genotypes.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504739 SCV000598995 likely pathogenic Retinal dystrophy 2015-01-01 no assertion criteria provided research

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