ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.4326C>A (p.Asn1442Lys)

gnomAD frequency: 0.00001  dbSNP: rs762150575
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480271 SCV000564534 pathogenic not provided 2023-06-16 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21911583, 23982839, 30834176, 30718709, 28559085, 23143460, 28005406, 30060493, 31589614, 36672932, 31964843)
Blueprint Genetics RCV001073593 SCV001239144 pathogenic Retinal dystrophy 2019-07-09 criteria provided, single submitter clinical testing
Invitae RCV000480271 SCV001375786 pathogenic not provided 2024-01-29 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1442 of the ABCA4 protein (p.Asn1442Lys). This variant is present in population databases (rs762150575, gnomAD 0.004%). This missense change has been observed in individual(s) with Stargardt disease or cone-rod dystrophy (PMID: 23143460, 23982839, 28559085, 30834176; Invitae). 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: 417991). 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 with a positive predictive value of 95%. This variant disrupts the p.Asn1442 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been observed in individuals with ABCA4-related conditions (PMID: 30060493), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet RCV000787780 SCV000926788 likely pathogenic Stargardt disease 2018-04-01 no assertion criteria provided research

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