Submissions for variant NM_000350.3(ABCA4):c.5714+5G>A

gnomAD frequency: 0.00036  dbSNP: rs61751407

Total submissions: 35

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000210321	SCV000281936	pathogenic	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000085757	SCV000321355	pathogenic	not provided	2024-12-17	criteria provided, single submitter	clinical testing	Minigene splice assays in HEK293 cells demonstrate that the c.5714+5G>A variant construct results in exon 40 skipping, which was confirmed by cDNA sequencing (PMID: 29162642, 28714225); This variant is associated with the following publications: (PMID: 37498587, 34906470, 11702214, 28365912, 32307445, 35076026, 37734845, 30903310, 30093795, 31429209, 32531858, 33706644, 34758253, 31456290, 10413692, 24265693, 25066811, 22328824, 17982420, 9466990, 21911583, 11328725, 19074458, 28341476, 26872967, 28118664, 28838317, 28044389, 29555955, 30771335, 30670881, 29925512, 31589614, 32619608, 34327195, 33302505, 32783370, 32815999, 32467599, 31980526, 32581362, 35836572, 35119454, 28714225, 35260635, 36209838, 37217489, 36460718, 29162642, 35120629, 31964843, 34321860, 36669873)
Eurofins Ntd Llc (ga)	RCV000085757	SCV000341399	pathogenic	not provided	2016-05-11	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778997	SCV000915438	pathogenic	ABCA4-related disorder	2018-09-07	criteria provided, single submitter	clinical testing	Across a selection of the available literature, the ABCA4 c.5714+5G>A variant, also referred to as IVS40+5G>A, has been identified in 26 individuals with Stargardt disease, including in one homozygote, 20 compound heterozygotes, and five heterozygotes in whom a second variant was not identified, and in six compound heterozygotes with cone-rod dystrophy (Cremers et al. 1998; Rivera et al. 2000; Gerth et al. 2002; Hargitai et al. 2005; Hwang et al. 2009; Cideciyan et al. 2009). The variant was also found in four unaffected family members in a heterozygous state. The variant was absent from 320 control individuals, but is reported at a frequency of 0.00151 in the European American population of the Exome Sequencing Project. RT-PCR analysis of transformed COS-7 cells revealed that the c.5714+5G>A variant generates both a correctly spliced and an incorrectly spliced product, suggesting aberrant splicing with a possibility of some residual activity of the ABCA4 protein (Rivera et al. 2000). Based on the collective evidence, the c.5714+5G>A variant is classified as pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Mendelics	RCV000210321	SCV001135329	pathogenic	Severe early-childhood-onset retinal dystrophy	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085757	SCV001217350	pathogenic	not provided	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change falls in intron 40 of the ABCA4 gene. It does not directly change the encoded amino acid sequence of the ABCA4 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs61751407, gnomAD 0.05%). This variant has been observed in individuals with autosomal recessive Stargardt disease and cone-rod dystrophy (PMID: 9466990, 10413692, 19074458). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 99403). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074898	SCV001240502	pathogenic	Retinal dystrophy	2019-08-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000085757	SCV001247603	pathogenic	not provided	2024-07-01	criteria provided, single submitter	clinical testing	ABCA4: PM3:Very Strong, PM2, PS3:Supporting
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000515694	SCV001365627	pathogenic	Stargardt disease	2019-05-08	criteria provided, single submitter	clinical testing	The c.5714+5G>A variant in ABCA4 is one of the most common variants in ABCA4 in patients with autosomal recessive Stargardt disease, accounting for up to 16% of disease-causing variants in this gene (Cremers 1998, River 2000, Smaragda 2018, Birtel 2018). It has also been identified in 71/129064 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 99403). This variant is located in the 5' splice region, and in vitro functional studies support an impact on protein function (Rivera 2000, Sangermano 2018). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Stargardt disease. ACMG/AMP Criteria applied: PM3_VeryStrong, PVS1_Strong, PP1.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196124	SCV001366611	pathogenic	Age related macular degeneration 2	2019-06-04	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PM3,PP3.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000085757	SCV001447613	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute of Medical Molecular Genetics, University of Zurich	RCV000210321	SCV001548065	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2021-01-30	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000210321	SCV001573567	pathogenic	Severe early-childhood-onset retinal dystrophy	2021-04-08	criteria provided, single submitter	research	The ABCA4 c.5714+5G>A 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: PVS1, PM2, PM3, PP1. Based on this evidence we have classified this variant as Pathogenic.
Genomics England Pilot Project, Genomics England	RCV000210303	SCV001760047	likely pathogenic	Retinitis pigmentosa 19		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000085757	SCV002018137	pathogenic	not provided	2023-03-23	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000210321	SCV002505619	pathogenic	Severe early-childhood-onset retinal dystrophy	2023-08-01	criteria provided, single submitter	clinical testing	Criteria applied: PM3_VSTR,PS4,PS3_MOD,PS1_SUP,PM2_SUP,PP1
Fulgent Genetics, Fulgent Genetics	RCV002498458	SCV002809894	pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2024-06-06	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004815127	SCV005070743	pathogenic	Optic atrophy	2023-01-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001074898	SCV005073468	pathogenic	Retinal dystrophy	2023-01-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000210321	SCV005087245	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 inherited retinal diseases (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. A mini gene assay showed that this variant led to two products; a correctly spliced one and one with exon 40 skipped (PMID: 29162642). (SP) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (highest allele count: 672 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in individuals with Stargardt (PMID: 10958763) and classified as pathogenic by multiple diagnostic laboratories in ClinVar. (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001074898	SCV005420687	likely pathogenic	Retinal dystrophy	2024-10-04	criteria provided, single submitter	research	PS3,PM3(strong),PM2,PP3
OMIM	RCV000332324	SCV000028553	pathogenic	Cone-rod dystrophy 3	2008-07-01	no assertion criteria provided	literature only
Retina International	RCV000085757	SCV000117898	not provided	not provided		no assertion provided	not provided
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV000210303	SCV000259077	pathogenic	Retinitis pigmentosa 19	2015-01-23	no assertion criteria provided	clinical testing
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV000210321	SCV000259089	pathogenic	Severe early-childhood-onset retinal dystrophy	2015-01-22	no assertion criteria provided	clinical testing
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000332324	SCV000536750	pathogenic	Cone-rod dystrophy 3	2015-07-23	no assertion criteria provided	research
Rui Chen Lab, Baylor College of Medicine	RCV000515694	SCV000579418	pathogenic	Stargardt disease	2017-05-09	no assertion criteria provided	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000210321	SCV000599001	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2015-01-01	no assertion criteria provided	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000515694	SCV000926481	likely pathogenic	Stargardt disease	2018-04-01	no assertion criteria provided	research
GenomeConnect, ClinGen	RCV000845081	SCV000986928	not provided	Stargardt disease; Cone-rod dystrophy		no assertion provided	phenotyping only	Variant interpretted as pathogenic and reported on 07/26/2017 by GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Sharon lab, Hadassah-Hebrew University Medical Center	RCV000515694	SCV001160825	pathogenic	Stargardt disease	2019-06-23	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000085757	SCV001955151	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000085757	SCV001966459	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	RCV000210321	SCV005049255	pathogenic	Severe early-childhood-onset retinal dystrophy		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV000778997	SCV005351186	pathogenic	ABCA4-related disorder	2024-09-18	no assertion criteria provided	clinical testing	The ABCA4 c.5714+5G>A variant is predicted to interfere with splicing. This variant (also known as IVS40+5G>A) has been reported in individuals with inherited retinal disease (see for examples Cremers et al. 1998. PubMed ID: 9466990; Klevering et al. 2004. PubMed ID: 15494742; Birtel et al. 2018. PubMed ID: 29555955). This variant is predicted to disrupt normal splicing (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751), and functional analysis by RT-PCR revealed that this variant indeed produces both normal and abnormal splicing products (Rivera et al. 2000. PubMed ID: 10958763). This variant is reported in 0.055% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/99403/). We classify this variant as pathogenic.