ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.4793C>A (p.Ala1598Asp) (rs61750155)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000408465 SCV000281906 likely pathogenic Stargardt disease 1 2016-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000085674 SCV000511901 pathogenic not provided 2018-10-10 criteria provided, single submitter clinical testing The A1598D variant in the ABCA4 gene has been reported previously in association with autosomal recessive ABCA4-related retinal dystrophies, including Stargardt disease, cone-rod dystrophy, and retinitis pigmentosa, when present in the homozygous state or when in trans with another disease-causing variant (Maugeri et al., 2000; Cideciyan et al., 2009; Abu-Safieh et al., 2013; Boulanger-Scemama et al., 2015; Tsipi et al., 2016; Verdina et al., 2017; Abed et al., 2018). The A1598D variant is observed in 3/33,512 (0.009%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. However, the A1598D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, a different missense variant at this same residue (A1598G) has been reported in association with Stargardt disease (Xin et al., 2015). We interpret A1598D as a pathogenic variant.
Invitae RCV000085674 SCV001213077 pathogenic not provided 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 1598 of the ABCA4 protein (p.Ala1598Asp). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is present in population databases (rs61750155, ExAC 0.009%). This variant has been observed in individual(s) affected with retinal disease (PMID: 10958761, 28559085, 23105016, 19074458, 19074458). 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: 99321). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Ala1598 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been observed in individuals with ABCA4-related conditions (PMID: 26161775), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001074177 SCV001239747 pathogenic Retinal dystrophy 2019-02-20 criteria provided, single submitter clinical testing
Retina International RCV000085674 SCV000117814 not provided not provided no assertion provided not provided
NEI Ophthalmic Genomics Laboratory,National Institutes of Health RCV000085674 SCV000119179 not provided not provided no assertion provided not provided
Sharon lab,Hadassah-Hebrew University Medical Center RCV001002825 SCV001160842 pathogenic Stargardt disease 2019-06-23 no assertion criteria provided research

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