ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.1761-2A>G

gnomAD frequency: 0.00001  dbSNP: rs754765164
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001386479 SCV001586713 pathogenic not provided 2025-01-13 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 12 of the ABCA4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ABCA4 are known to be pathogenic (PMID: 10958761, 24938718, 25312043, 26780318). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with cone-rod dystrophy (PMID: 26780318). 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: 1073468). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics, Royal Melbourne Hospital RCV002225134 SCV002503675 likely pathogenic Severe early-childhood-onset retinal dystrophy 2023-03-30 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 13 of ABCA4. It is expected to disrupt RNA splicing and likely results in exon 13 skipping, which would likely disrupt the protein product by removing 59 amino acids in the first extracellular domain. Loss of function is a well established mechanism of disease (PVS1_Moderate). The variant is present in a large population cohort at a frequency of 0.0008%, which is consistent with recessive disease (rs754765164, 2/249,438 alleles, 0 homozygotes in gnomAD v2.1.1 - PM2). It has been identified as homozygous in a retinitis pigmentosa case (DOI: 10.3760/cma.j.issn.1674-845X.2016.03.005), and is confirmed compound heterozygous with a pathogenic missense variant (p.Arg602Trp) in a Stargardt disease patient in this laboratory (PM3). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1_Moderate, PM2, PM3.
Fulgent Genetics, Fulgent Genetics RCV005038198 SCV005661436 likely pathogenic Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19 2024-03-16 criteria provided, single submitter clinical testing

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