Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ce |
RCV000488184 | SCV000574769 | likely pathogenic | not provided | 2019-02-01 | criteria provided, single submitter | clinical testing | |
Molecular Genetics Laboratory, |
RCV001199608 | SCV001162372 | pathogenic | Isolated macular dystrophy | 2020-01-09 | criteria provided, single submitter | research | |
Illumina Laboratory Services, |
RCV001099950 | SCV001256443 | uncertain significance | ABCA4-Related Disorders | 2018-01-12 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. |
Invitae | RCV000488184 | SCV001373838 | likely pathogenic | not provided | 2024-01-11 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 959 of the ABCA4 protein (p.Thr959Ser). This variant is present in population databases (rs368846708, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of ABCA4-related conditions (PMID: 32531858). ClinVar contains an entry for this variant (Variation ID: 424902). 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.Thr959 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10958763, 24097981). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV003235244 | SCV003934464 | uncertain significance | not specified | 2023-05-22 | criteria provided, single submitter | clinical testing | Variant summary: ABCA4 c.2875A>T (p.Thr959Ser) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251358 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ABCA4 causing Retinitis Pigmentosa (7.2e-05 vs 0.0014), allowing no conclusion about variant significance. c.2875A>T has been reported in the literature in an individual affected with retinal degeneration (example: Weisschuh_2020). These data do not allow any conclusion about variant significance. 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: 31964843, 32531858). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and pathogenic/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. |