Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000493611 | SCV000581934 | uncertain significance | not provided | 2017-11-08 | criteria provided, single submitter | clinical testing | The c.4128 G>A variant has been published previously in association with Stargardt disease (Sodi et al., 2016). The variant is not observed in large population cohorts (Lek et al., 2016). This synonymous variant occurs at a nucleotide that is conserved across species. In silico analysis predicts this variant is destroys the natural splice donor site of exon 27. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
Illumina Laboratory Services, |
RCV001099858 | SCV001256347 | uncertain significance | ABCA4-Related Disorders | 2017-04-27 | criteria provided, single submitter | clinical testing | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. |
Invitae | RCV000493611 | SCV002216210 | likely pathogenic | not provided | 2022-04-16 | criteria provided, single submitter | clinical testing | This sequence change affects codon 1376 of the ABCA4 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ABCA4 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 4 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Stargardt disease (PMID: 19265867; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 429378). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in the activation of a cryptic splice site in exon 27 (PMID: 29162642). 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. |
Prevention |
RCV003409681 | SCV004114228 | likely pathogenic | ABCA4-related condition | 2022-09-26 | criteria provided, single submitter | clinical testing | The ABCA4 c.4128G>A variant is not predicted to result in an amino acid change (p.=). While this variant is not predicted to cause an amino acid substitution, this variant affects the last nucleotide of exon 27 and is predicted to abolish this canonical splice site based on available splicing prediction programs (Alamut Visual v2.11). A functional study using a midigene splicing assay confirmed this prediction, finding that this variant leads to 0% correctly spliced mRNA; the authors classified this variant as severe (Sangermano et al. 2018. PubMed ID: 29162642). This variant has been reported in the compound heterozygous state in individuals with Stargardt disease (reported as "Q1376 splice" in Passerini et al. 2010. PubMed ID: 19265867; Dhaenens et al. 2019. ARVO Annual Meeting Abstract https://iovs.arvojournals.org/article.aspx?articleid=2744355). This variant has not been documented in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Given the evidence, we interpret c.4128G>A (p.=) as likely pathogenic. |