ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.5461-10T>C (rs1800728)

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Total submissions: 22
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078669 SCV000229932 pathogenic not provided 2017-05-24 criteria provided, single submitter clinical testing
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000177965 SCV000281925 pathogenic Stargardt disease 1 2016-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000078669 SCV000321356 pathogenic not provided 2018-08-11 criteria provided, single submitter clinical testing The c.5461-10 T>C variant in the ABCA4 gene has been reported previously in the homozygous state and in the presence of a second ABCA4 pathogenic variant, in association with Stargardt disease and cone-rod dystrophy (Webster et al., 2001; Klevering et al., 2005; Burke et al., 2010; Alapati et al., 2014; Sangermano et al., 2016). A minigene splice assay in HEK293T cells showed the c.5461-10 T>C variant construct had 100% exon 39 skipping, which was confirmed by cDNA sequencing (Sangermano et al., 2016). Furthermore, a study examining the RNA from the fibroblast cells from individuals harboring the c.5461-10 T>C variant identified a reduction in full-length mRNA and the presence of alternatively splice mRNAs where exons 39-40 were skipped (Aukrust et al., 2017). The c.5461-10 T>C variant is reported as likely pathogenic in ClinVar by a different clinical laboratory, but additional evidence is not available (ClinVar SCV000229932.3, Landrum et al., 2016). The c.5461-10 T>C variant is observed in 59/126,148 (0.05%) alleles from individuals of non-Finnish European background, with no homozygous individuals reported, in large population cohorts (Lek et al., 2016). This nucleotide substitution occurs at a position that is conserved in mammals. We interpret c.5461-10 T>C as a pathogenic variant.
Fulgent Genetics,Fulgent Genetics RCV000763440 SCV000894207 pathogenic Cone-rod dystrophy 3; Age-related macular degeneration 2; Stargardt disease 1; Retinitis pigmentosa 19 2018-10-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000430 SCV001157244 likely pathogenic not specified 2018-09-23 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000177965 SCV001164562 likely pathogenic Stargardt disease 1 2018-12-03 criteria provided, single submitter research The heterozygous c.5461-10T>C variant in ABCA4 was identified by our study in the compound heterozygous state, with a likely pathogenic variant, in one individual with Stargardt disease. This variant has been identified in 0.02278% (63/276528) of chromosomes and by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1800728). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The allele frequency of this variant in a cohort of 139 individuals diagnosed with Stargardt disease and multiple missense variants in the ABCA4 gene was approximately 5% (PMID: 29925512). The presence of this variant in combination with a likely pathogenic variant increases the likelihood that the c.5461-10T>C variant is pathogenic. In vitro functional studies provide some evidence that the c.5461-10T>C variant may impact protein function by causing abnormal splicing of Exon 39 and 40 in many cell types, leading to a frameshift and early termination of the protein (PMID: 29461686). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PS3, PM3_Supporting (Richards 2015).
Invitae RCV000078669 SCV001230708 pathogenic not provided 2020-01-10 criteria provided, single submitter clinical testing This sequence change falls in intron 38 of the ABCA4 gene. It does not directly change the encoded amino acid sequence of the ABCA4 protein. This variant is present in population databases (rs1800728, ExAC 0.04%). This variant has been observed in several individuals with Stargardt disease and has been observed to segregate with this condition in at least one family (PMID: 23695285, 22328824, 29310964, 10958763, 23443024). This variant is also known as IVS38-10T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 92870). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 27775217, 29461686, 26976702). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV000210327 SCV001239244 pathogenic Retinal dystrophy 2019-08-16 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000078669 SCV001247605 pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196637 SCV001367257 pathogenic Visual impairment; Retinal dystrophy; Reduced visual acuity 2019-08-23 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BS2. This variant was detected in hemizygous state.
OMIM RCV000008366 SCV000028574 pathogenic Cone-rod dystrophy 3 2008-07-01 no assertion criteria provided literature only
Retina International RCV000078669 SCV000117870 not provided not provided no assertion provided not provided
Centre for Genomic Medicine, Manchester,Central Manchester University Hospitals RCV000210325 SCV000259075 likely pathogenic Bull's eye maculopathy 2015-01-19 no assertion criteria provided clinical testing
Centre for Genomic Medicine, Manchester,Central Manchester University Hospitals RCV000210327 SCV000259078 likely pathogenic Retinal dystrophy 2015-01-21 no assertion criteria provided clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000008366 SCV000536892 pathogenic Cone-rod dystrophy 3 2016-02-23 no assertion criteria provided research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504857 SCV000598996 likely pathogenic Macular dystrophy 2015-01-01 no assertion criteria provided research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000210327 SCV000598997 likely pathogenic Retinal dystrophy 2015-01-01 no assertion criteria provided research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000177965 SCV000598998 likely pathogenic Stargardt disease 1 2015-01-01 no assertion criteria provided research
Human Genetics - Radboudumc,Radboudumc RCV000678511 SCV000804582 pathogenic Age-related macular degeneration 2 2016-09-01 no assertion criteria provided clinical testing
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787510 SCV000926476 pathogenic Retinitis pigmentosa 2018-04-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000504857 SCV000926477 pathogenic Macular dystrophy 2018-04-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787771 SCV000926776 pathogenic Stargardt disease 2018-04-01 no assertion criteria provided research

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