Total submissions: 40
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Eurofins Ntd Llc |
RCV000078669 | SCV000229932 | pathogenic | not provided | 2017-05-24 | criteria provided, single submitter | clinical testing | |
Institute of Human Genetics, |
RCV000177965 | SCV000281925 | pathogenic | Severe early-childhood-onset retinal dystrophy | 2016-01-01 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000078669 | SCV000321356 | pathogenic | not provided | 2022-07-06 | criteria provided, single submitter | clinical testing | A study examining the RNA from fibroblast cells from individuals harboring the c.5461-10 T>C variant identified a reduction in full-length mRNA and the presence of alternatively spliced mRNAs where exons 39-40 were skipped (Aukrust et al., 2017); 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); This variant is associated with the following publications: (PMID: 25525159, 28044389, 15494742, 18024811, 27775217, 15614537, 26976702, 10090887, 11328725, 20696155, 26261413, 25082885, 10958763, 29162642, 29461686, 29925512, 22328824, 11527935, 22264887, 19074458, 23695285, 24713488, 26393467, 15161829, 26568636, 23918662, 26872967, 26527198, 26311262, 27583828, 25097241, 23591405, 25363634, 28130426, 29126757, 28446513, 32467599, 32141364, 28947085, 29310964, 28341476, 30093795, 30634128, 30643219, 31618761, 30204727, 30576320, 31980526, 30718709, 31589614, 32619608, 34570182, 32783370, 33851411, 34198153) |
Fulgent Genetics, |
RCV000763440 | SCV000894207 | pathogenic | Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
ARUP Laboratories, |
RCV001000430 | SCV001157244 | likely pathogenic | not specified | 2018-09-23 | criteria provided, single submitter | clinical testing | |
Broad Center for Mendelian Genomics, |
RCV000177965 | SCV001164562 | likely pathogenic | Severe early-childhood-onset retinal dystrophy | 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). |
Labcorp Genetics |
RCV000078669 | SCV001230708 | pathogenic | not provided | 2025-02-03 | 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. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs1800728, gnomAD 0.05%). This variant has been observed in individuals with Stargardt disease (PMID: 10958763, 22328824, 23443024, 23695285, 29310964). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS38-10T>C. ClinVar contains an entry for this variant (Variation ID: 92870). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 26976702, 27775217, 29461686). 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 | |
Ce |
RCV000078669 | SCV001247605 | pathogenic | not provided | 2023-11-01 | criteria provided, single submitter | clinical testing | ABCA4: PM3:Very Strong, PM2, PS3:Supporting |
Centre for Mendelian Genomics, |
RCV000678511 | SCV001367257 | pathogenic | Age related macular degeneration 2 | 2019-08-23 | criteria provided, single submitter | clinical testing | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM3,PP4. |
Institute of Medical Genetics and Applied Genomics, |
RCV000078669 | SCV001447236 | pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
Ocular Genomics Institute, |
RCV000177965 | SCV001573552 | pathogenic | Severe early-childhood-onset retinal dystrophy | 2021-04-08 | criteria provided, single submitter | research | The ABCA4 c.5461-10T>C 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. |
Genomics England Pilot Project, |
RCV001542559 | SCV001760049 | pathogenic | Retinitis pigmentosa 19 | criteria provided, single submitter | clinical testing | ||
Institute of Human Genetics, |
RCV000008366 | SCV001950069 | pathogenic | Cone-rod dystrophy 3 | 2021-08-03 | criteria provided, single submitter | clinical testing | This variant was identified as compound heterozygous with NM_000350.3:c.1822T>A. |
Revvity Omics, |
RCV000078669 | SCV002019733 | pathogenic | not provided | 2021-04-13 | criteria provided, single submitter | clinical testing | |
Institute of Human Genetics, |
RCV000177965 | SCV002072543 | pathogenic | Severe early-childhood-onset retinal dystrophy | 2022-01-17 | criteria provided, single submitter | clinical testing | This variant was identified as compound heterozygous with NM_000350.3:c.67-2A>G._x000D_ Criteria applied: PS3, PS4, PM3_STR, PM2_SUP, PP1 |
Ophthalmic Genetics Group, |
RCV000787771 | SCV004030353 | pathogenic | Stargardt disease | 2023-07-24 | criteria provided, single submitter | research | Clinical significance based on ACMG v2.0 |
Institute of Human Genetics, |
RCV000210327 | SCV005073473 | pathogenic | Retinal dystrophy | 2023-01-01 | criteria provided, single submitter | clinical testing | |
Institute of Human Genetics, |
RCV000678511 | SCV005397122 | pathogenic | Age related macular degeneration 2 | 2024-10-18 | criteria provided, single submitter | clinical testing | Criteria applied: PS3,PS4,PM3_STR,PM2_SUP,PP1 |
Victorian Clinical Genetics Services, |
RCV000177965 | SCV005398826 | pathogenic | Severe early-childhood-onset retinal dystrophy | 2024-10-08 | 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) and other eye conditions (OMIM). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. (PMID: 31522899). (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. Patient derived fibroblasts demonstrated two possible splicing outcomes, skipping of exon 39 or skipping of both exons 39 and 40 (PMID: 27775217, 36209838). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (62 heterozygotes, 0 homozygotes). (SP) 0704 - Another splice variant comparable to the one identified in this case has limited previous evidence for pathogenicity. c.5461-10T>G has been reported once in ClinVar as pathogenic. This variant was identified in an individual affected with cone rod dystrophy. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic many times (ClinVar) and is seen in the literature in compound heterozygous individuals, most commonly presenting with autosomal recessive Stargardt disease 1 (MIM#248200) (PMID: 31766579). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
Al Jalila Children’s Genomics Center, |
RCV000210327 | SCV005420705 | pathogenic | Retinal dystrophy | 2024-10-04 | criteria provided, single submitter | research | PS3,PS1,PM3(strong), PM2, PP1 |
Ambry Genetics | RCV004975272 | SCV005581691 | pathogenic | Inborn genetic diseases | 2024-11-01 | criteria provided, single submitter | clinical testing | The c.5461-10T>C intronic alteration results from a T to C substitution 10 nucleotides before coding exon 39 of the ABCA4 gene. Based on data from gnomAD, the C allele has an overall frequency of 0.022% (62/282194) total alleles studied. The highest observed frequency was 0.045% (58/128638) of European (non-Finnish) alleles. This variant has been identified in the homozygous state and in conjunction with other ABCA4 variants in individuals with Stargardt disease and/or clinical features consistent with ABCA4-related retinal dystrophy (Jonsson, 2013; Heathfield, 2013; Sangermano, 2016; Stone, 2017; Khan, 2018; Fujinami, 2019; Pfau, 2022). This nucleotide position is highly conserved in available vertebrate species. A functional study demonstrates this variant results in exon skipping (Sangermano, 2016). In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Based on the available evidence, this alteration is classified as pathogenic. |
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, |
RCV000210325 | SCV000259075 | likely pathogenic | Benign concentric annular macular dystrophy | 2015-01-19 | no assertion criteria provided | clinical testing | |
Centre for Genomic Medicine, |
RCV000210327 | SCV000259078 | likely pathogenic | Retinal dystrophy | 2015-01-21 | no assertion criteria provided | clinical testing | |
Division of Human Genetics, |
RCV000008366 | SCV000536892 | pathogenic | Cone-rod dystrophy 3 | 2016-02-23 | no assertion criteria provided | research | |
NIHR Bioresource Rare Diseases, |
RCV000504857 | SCV000598996 | likely pathogenic | Macular dystrophy | 2015-01-01 | no assertion criteria provided | research | |
NIHR Bioresource Rare Diseases, |
RCV000210327 | SCV000598997 | likely pathogenic | Retinal dystrophy | 2015-01-01 | no assertion criteria provided | research | |
NIHR Bioresource Rare Diseases, |
RCV000177965 | SCV000598998 | likely pathogenic | Severe early-childhood-onset retinal dystrophy | 2015-01-01 | no assertion criteria provided | research | |
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000678511 | SCV000804582 | pathogenic | Age related macular degeneration 2 | 2016-09-01 | no assertion criteria provided | clinical testing | |
Department of Clinical Genetics, |
RCV000787510 | SCV000926476 | pathogenic | Retinitis pigmentosa | 2018-04-01 | no assertion criteria provided | research | |
Department of Clinical Genetics, |
RCV000504857 | SCV000926477 | pathogenic | Macular dystrophy | 2018-04-01 | no assertion criteria provided | research | |
Department of Clinical Genetics, |
RCV000787771 | SCV000926776 | pathogenic | Stargardt disease | 2018-04-01 | no assertion criteria provided | research | |
Genome Diagnostics Laboratory, |
RCV000078669 | SCV001808250 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics, |
RCV000078669 | SCV001923567 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000078669 | SCV001974988 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Human Development and Health, |
RCV000078669 | SCV002106371 | not provided | not provided | no assertion provided | in vitro | ||
Ophthalmo- |
RCV000177965 | SCV005048923 | pathogenic | Severe early-childhood-onset retinal dystrophy | no assertion criteria provided | research | ||
Prevention |
RCV004732655 | SCV005344777 | pathogenic | ABCA4-related disorder | 2024-06-03 | no assertion criteria provided | clinical testing | The ABCA4 c.5461-10T>C variant is predicted to interfere with splicing. This intronic variant is also known as IVS38-10T>C and has been frequently reported in both the homozygous and compound heterozygous states in patients with Stargardt disease (see for examples Rivera et al. 2000. PubMed ID: 10958763; Roberts et al. 2012. PubMed ID: 22328824; Heathfield et al. 2013. PubMed ID: 23695285). A functional study using a mini-gene assay revealed that this variant causes exon skipping and results in truncated ABCA4 protein (Sangermano et al. 2016. PubMed ID: 26976702, Figure 4). This variant has been interpreted as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/92870). This variant is reported in 0.045% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Given all the evidence, we interpret c.5461-10T>C as pathogenic. |