Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000085639 | SCV001224356 | pathogenic | not provided | 2023-12-30 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 1488 of the ABCA4 protein (p.Cys1488Phe). This variant is present in population databases (rs61750147, gnomAD 0.002%). This missense change has been observed in individuals with Stargardt disease (PMID: 20647261; Invitae). ClinVar contains an entry for this variant (Variation ID: 99286). 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.Cys1488 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22449572, 28559085, 29555955, 29925512). 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. |
| Molecular Genetics, |
RCV002225081 | SCV002503668 | likely pathogenic | Severe early-childhood-onset retinal dystrophy | 2022-04-22 | criteria provided, single submitter | clinical testing | This sequence change is predicted to replace cysteine with phenylalanine at codon 1488 of the ABCA4 protein, p.(Cys1488Phe). The cysteine residue is highly conserved (100 vertebrates, UCSC), and is predicted to form a disulphide bond. There is a large physicochemical difference between cysteine and phenylalanine. The variant is present in a large population cohort at a frequency of 0.0008%, which is consistent with recessive disease (rs61750147, 2/243,254 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified in at least one Stargardt disease case with another pathogenic variant (PMID: 11673412). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms). Two different missense changes at the same position (p.Cys1488Tyr, p.Cys1488Arg) determined to be likely pathogenic/pathogenic have been seen before (ClinVar IDs: 99284, 99285). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as LIKELY PATHOGENIC . Following criteria are met: PM2, PM5, PM3_Supporting, PP3. |
| Victorian Clinical Genetics Services, |
RCV002470764 | SCV002767513 | pathogenic | Cone-rod dystrophy 3 | 2020-10-19 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 5-Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Stargardt disease (MIM #248200), cone-rod dystrophy 3 (MIM #6041163), fundus flavimaculatus (MIM #248200), early-onset severe Retinal dystrophy (MIM #248200) and retinitis pigmentosa 19 (MIM #601718). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0701 - Other missense variants comparable to the one identified in this case has very strong previous evidence for pathogenicity. The p.(Cys1488Arg) and p.(Cys1488Tyr) variants have been identified in multiple individuals with Stargardt disease (ClinVar; PMIDs: 22449572, 23769331, 29854428, 31766579, 30820146). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been identified in at least three individuals with Stargardt disease (Clinvar; PMID: 11328725). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000350.2(ABCA4):c.4918C>T; p.(Arg1640Trp)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (VCGS #20G001628). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Retina International | RCV000085639 | SCV000117778 | not provided | not provided | no assertion provided | not provided |