ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.6122G>A (p.Gly2041Asp)

gnomAD frequency: 0.00001  dbSNP: rs1462350577
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Medical Molecular Genetics, University of Zurich RCV001352992 SCV001548084 likely pathogenic Severe early-childhood-onset retinal dystrophy 2021-01-30 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002548492 SCV003523328 pathogenic not provided 2023-10-17 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 2041 of the ABCA4 protein (p.Gly2041Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Stargardt disease (PMID: 18652558, 20801516, 31884623, 33546218). ClinVar contains an entry for this variant (Variation ID: 1048145). 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. This variant disrupts the p.Gly2041 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004699329 SCV005203829 uncertain significance not specified 2024-07-02 criteria provided, single submitter clinical testing Variant summary: ABCA4 c.6122G>A (p.Gly2041Asp) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251330 control chromosomes. c.6122G>A has been reported in the literature in individuals affected with Stargardt Disease in either the compound heterozygous state or heterozygous with an unspecified second variant (e.g. Schlottmann_2023, Stenirri_2008, Maggi_2021, Cornelis_2022, Tiwari_2016, Booij_2011). These data indicate that the variant may be associated with disease. 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: 20801516, 35120629, 33546218, 37217489, 18652558, 27353947). ClinVar contains an entry for this variant (Variation ID: 1048145). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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