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

Total submissions: 22

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