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

gnomAD frequency: 0.00029  dbSNP: rs1800728

Total submissions: 40

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
GeneDx	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, 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, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000430	SCV001157244	likely pathogenic	not specified	2018-09-23	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	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 (formerly Invitae), Labcorp	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
CeGaT Center for Human Genetics Tuebingen	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, University Medical Centre Ljubljana	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, University Hospital Tübingen	RCV000078669	SCV001447236	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	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, Genomics England	RCV001542559	SCV001760049	pathogenic	Retinitis pigmentosa 19		criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	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, Revvity	RCV000078669	SCV002019733	pathogenic	not provided	2021-04-13	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	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, Institute of Molecular and Clinical Ophthalmology Basel	RCV000787771	SCV004030353	pathogenic	Stargardt disease	2023-07-24	criteria provided, single submitter	research	Clinical significance based on ACMG v2.0
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000210327	SCV005073473	pathogenic	Retinal dystrophy	2023-01-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	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, Murdoch Childrens Research Institute	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, Al Jalila Childrens Speciality Hospital	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, Manchester, Central Manchester University Hospitals	RCV000210325	SCV000259075	likely pathogenic	Benign concentric annular macular dystrophy	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	Severe early-childhood-onset retinal dystrophy	2015-01-01	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000678511	SCV000804582	pathogenic	Age related macular degeneration 2	2016-09-01	no assertion criteria provided	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787510	SCV000926476	pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000504857	SCV000926477	pathogenic	Macular dystrophy	2018-04-01	no assertion criteria provided	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787771	SCV000926776	pathogenic	Stargardt disease	2018-04-01	no assertion criteria provided	research
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000078669	SCV001808250	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000078669	SCV001923567	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000078669	SCV001974988	pathogenic	not provided		no assertion criteria provided	clinical testing
Human Development and Health, University of Southampton	RCV000078669	SCV002106371	not provided	not provided		no assertion provided	in vitro
Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	RCV000177965	SCV005048923	pathogenic	Severe early-childhood-onset retinal dystrophy		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	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.