ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.4539+2028C>T

gnomAD frequency: 0.00004  dbSNP: rs869320785
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV001074348 SCV001239923 pathogenic Retinal dystrophy 2019-07-16 criteria provided, single submitter clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear RCV000408506 SCV001573460 pathogenic Severe early-childhood-onset retinal dystrophy 2021-04-08 criteria provided, single submitter research The ABCA4 c.4539+2028C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PS3, PM3-S. Based on this evidence we have classified this variant as Pathogenic.
Invitae RCV001380975 SCV001579215 pathogenic not provided 2024-01-10 criteria provided, single submitter clinical testing This sequence change falls in intron 30 of the ABCA4 gene. It does not directly change the encoded amino acid sequence of the ABCA4 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (no rsID available, gnomAD 0.03%). This variant has been observed in individual(s) with Stargardt disease (PMID: 23918662). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 236116). Studies have shown that this variant results in pseudoexon inclusion and introduces a premature termination codon (PMID: 29526278). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001380975 SCV002513144 pathogenic not provided 2022-04-28 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect with insertion of a 345 bp pseudoexon containing a stop codon, and the resulting transcript was subject to nonsense-mediated decay (Albert et al., 2018); This variant is associated with the following publications: (PMID: 26527198, 28118664, 23918662, 28771251, 29526278)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000408506 SCV002769542 pathogenic Severe early-childhood-onset retinal dystrophy 2021-05-06 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Stargardt disease 1 (MIM#248200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Affected siblings can have variable age of onset and severity of disease (PMID:31522899). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein due to the insertion of a retina-specific 345-nt pseudoexon (predicted protein change: p.Arg1514Leufs*36) (PMID: 29526278). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3) (6 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times in Stargardt disease patients. Many of these patients have this variant in cis with c.302+68C>T (ClinVar, PMIDs: 32627976; 32307445; 25082829; 23918662). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. By generating photoreceptor precursor cells (PPCs) from fibroblasts obtained from individuals with STGD1, it was demonstrated this deep-intronic variant results in a retina-specific 345-nt pseudoexon insertion (predicted protein change: p.Arg1514Leufs*36), likely due to the creation of exonic enhancers. This variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein. (PMID: 29526278). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Preventiongenetics, part of Exact Sciences RCV003390977 SCV004110176 pathogenic ABCA4-related condition 2023-02-23 criteria provided, single submitter clinical testing The ABCA4 c.4539+2028C>T variant is predicted to interfere with splicing. This variant was reported in individuals with Stargardt disease (Table 1, Braun et al. 2013. PubMed ID: 23918662; Table S2, Lionel et al. 2017. PubMed ID: 28771251; Fadaie et al. 2021. PubMed ID: 34795310). This variant is reported in 0.029% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-94492973-G-A). This variant was interpreted as uncertain (Table S2, Schulz et al. 2017. PubMed ID: 28118664). RNA studies suggest that this variant leds to a retina-specific 345-nt pseudoexon insertion (Albert et al. 2018. PubMed ID: 29526278). This variant is mainly interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/236116/). We interpreted this variant as pathogenic.
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg RCV000408506 SCV000281895 uncertain significance Severe early-childhood-onset retinal dystrophy 2016-01-01 flagged submission clinical testing
Clinical Genetics, Academic Medical Center RCV001380975 SCV001917278 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV001380975 SCV001966088 pathogenic not provided no assertion criteria provided clinical testing

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