Total submissions: 8
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000085839 | SCV000329044 | pathogenic | not provided | 2021-10-26 | criteria provided, single submitter | clinical testing | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 11328725, 11726554, 9973280, 11527935, 17982420, 24713488) |
| Eurofins Ntd Llc |
RCV000085839 | SCV000707203 | pathogenic | not provided | 2017-04-18 | criteria provided, single submitter | clinical testing | |
| Blueprint Genetics | RCV001075620 | SCV001241247 | pathogenic | Retinal dystrophy | 2019-02-07 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000085839 | SCV001413936 | pathogenic | not provided | 2024-01-24 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Lys223Metfs*14) in the ABCA4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCA4 are known to be pathogenic (PMID: 10958761, 24938718, 25312043, 26780318). This variant is present in population databases (rs63749080, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Stargardt disease or generalized choriocapillaris dystrophy (PMID: 9973280, 24713488). ClinVar contains an entry for this variant (Variation ID: 99478). For these reasons, this variant has been classified as Pathogenic. |
| Institute of Human Genetics, |
RCV001723670 | SCV001950070 | pathogenic | Severe early-childhood-onset retinal dystrophy | 2021-07-02 | criteria provided, single submitter | clinical testing | This variant was identified as compound heterozygous with NM_000350.3:c.286A>G. |
| Broad Center for Mendelian Genomics, |
RCV002513926 | SCV003761282 | pathogenic | Retinitis pigmentosa 19 | 2023-01-25 | criteria provided, single submitter | curation | The heterozygous p.Lys223MetfsTer14 variant in ABCA4 was identified by our study, in the compound heterozygous state with another pathogenic variant (ClinVar Variation ID: 265012). This individual also carried another pathogenic variant (ClinVar Variation ID: 265012); however, the phase of these variants is unknown at this time. The p.Lys223MetfsTer14 in ABCA4 has been previously reported in at least three unrelated individuals with autosomal recessive ABCA4-related retinopathy (PMID: 24713488, PMID: 11527935, PMID: 11726554, PMID: 11328725, SCV001950070.1) but has been identified in 0.006% (1/16252) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs63749081). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 99478) and has been interpreted as pathogenic by multiple submitters. These three previously reported unrelated individuals were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 24713488, ClinVar Variation ID: 99307, 7879; SCV001950070.1, ClinVar Variation ID: 99166), and the individual identified by our study was a compound heterozygote who carried a pathogenic variant with unknown phase (ClinVar Variation ID: 99166) which increases the likelihood that the p.Lys223MetfsTer14 variant is pathogenic. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 223 and leads to a premature termination codon 14 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the ABCA4 gene is an established disease mechanism in autosomal recessive ABCA4-related retinopathy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive ABCA4-related retinopathy. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_Strong (Richards 2015). |
| Retina International | RCV000085839 | SCV000117979 | not provided | not provided | flagged submission | not provided | ||
| Retina International | RCV000085839 | SCV000117982 | not provided | not provided | no assertion provided | not provided |