Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Institute of Human Genetics, |
RCV000408470 | SCV000281929 | likely pathogenic | Severe early-childhood-onset retinal dystrophy | 2016-01-01 | criteria provided, single submitter | clinical testing | |
| 3billion, |
RCV000408470 | SCV002058447 | likely pathogenic | Severe early-childhood-onset retinal dystrophy | 2022-01-03 | criteria provided, single submitter | clinical testing | Same nucleotide change resulting in same amino acid change has been previously reported to be associated with ABCA4 related disorder (ClinVar ID: VCV000236134, PMID:28118664, PS1_P). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099380,VCV000236133, PMID:9973280,15192030,23755871, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.933, 3CNET: 0.976, PP3_P). A missense variant is a common mechanism associated with Stargardt disease 1 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. |
| Labcorp Genetics |
RCV001854787 | SCV002238976 | pathogenic | not provided | 2021-09-29 | criteria provided, single submitter | clinical testing | 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 sequence change replaces histidine with arginine at codon 1838 of the ABCA4 protein (p.His1838Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individuals with Stargardt disease (PMID: 28118664; Invitae). ClinVar contains an entry for this variant (Variation ID: 236134). Experimental studies have shown that this missense change affects ABCA4 function (PMID: 33375396). This variant disrupts the p.His1838 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28771251; 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. |
| Institute of Human Genetics, |
RCV004816421 | SCV005069797 | likely pathogenic | Retinal dystrophy | 2019-01-01 | criteria provided, single submitter | clinical testing |