ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.6286G>A (p.Glu2096Lys)

gnomAD frequency: 0.00001  dbSNP: rs61750646
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000085804 SCV000344272 uncertain significance not provided 2016-09-02 criteria provided, single submitter clinical testing
GeneDx RCV000085804 SCV000616627 pathogenic not provided 2017-10-24 criteria provided, single submitter clinical testing The E2096K variant in the ABCA4 gene has been published previously in association with Stargardt disease (Lewis et al., 1999; Shroyer et al., 2001; Utz et al., 2013). The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). E2096K 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. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, E2096K has been shown to significantly reduce ATPase activity of the ABCA4 protein (Sun et al., 2000). In summary, we consider this variant to be pathogenic
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000085804 SCV001448852 pathogenic not provided 2019-06-19 criteria provided, single submitter clinical testing
Invitae RCV000085804 SCV004292358 pathogenic not provided 2023-06-03 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 11017087). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA4 protein function. ClinVar contains an entry for this variant (Variation ID: 99445). This missense change has been observed in individual(s) with Stargardt disease (PMID: 11726554, 29925512, 33691693). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs61750646, gnomAD 0.007%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2096 of the ABCA4 protein (p.Glu2096Lys).
Retina International RCV000085804 SCV000117947 not provided not provided no assertion provided not provided

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