Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Broad Center for Mendelian Genomics, |
RCV001005006 | SCV001164567 | uncertain significance | Cone-rod dystrophy 3 | 2018-12-03 | criteria provided, single submitter | research | The heterozygous p.Lys583Asn variant in ABCA4 was identified by our study in the compound heterozygous state with another VUS in one individual with cone rod dystrophyy. This variant has been identified in 0.002844% (7/246160) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs145265791). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Lys583Asn variant in ABCA4 has been reported in two individuals, one with Stargardt disease and one with a "ABCA4-associated retinal disease" (PMID: 23982839, 29343940). In summary, the clinical significance of the p.Lys583Asn variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3 (Richards 2015). |
| Blueprint Genetics | RCV001075802 | SCV001241437 | likely pathogenic | Retinal dystrophy | 2019-07-11 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001377733 | SCV001575135 | pathogenic | not provided | 2024-01-02 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 583 of the ABCA4 protein (p.Lys583Asn). This variant is present in population databases (rs145265791, gnomAD 0.04%). This missense change has been observed in individuals with clinical features of Stargardt disease (PMID: 29343940, 32307445; Invitae). ClinVar contains an entry for this variant (Variation ID: 814001). 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.Lys583 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been observed in individuals with ABCA4-related conditions (PMID: 26593885), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003331020 | SCV004037981 | uncertain significance | not specified | 2023-08-18 | criteria provided, single submitter | clinical testing | Variant summary: ABCA4 c.1749G>C (p.Lys583Asn) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251390 control chromosomes (gnomAD). c.1749G>C has been reported in the literature in individuals affected with Inherited Retinal Disease (e.g. Fujinami_2013, Dineiro_2020, Karali_2022) and Stargardt Disease (e.g. Bryant_2017, Khan_2020). 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: 29343940, 32483926, 23982839, 32307445, 36460718, 36672815). Three ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, one as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |