Submissions for variant NM_000350.3(ABCA4):c.6089G>A (p.Arg2030Gln)

gnomAD frequency: 0.00048  dbSNP: rs61750641

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000085787	SCV000230645	pathogenic	not provided	2016-08-10	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000178545	SCV000281948	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000085787	SCV000329050	pathogenic	not provided	2021-07-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a mild damaging effect (Curtis et al., 2020); This variant is associated with the following publications: (PMID: 32467599, 27535533, 32845050, 31456290, 30798147, 30215852, 30718709, 23891399, 29555955, 18854780, 26103963, 24265693, 24713488, 28118664, 28044389, 27820952, 27596865, 11379881, 11527935, 27491360, 9973280, 25283059, 28559085, 29925512)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000085787	SCV000883316	likely pathogenic	not provided	2017-06-02	criteria provided, single submitter	clinical testing	The ABCA4 c.6089G>A;p.Arg2030Gln variant has been published in several individuals with Stargardt disease and other ABVA4-related disorders (Bertelsen 2014, Cideciyan 2005, Duncker 2015, Jaakson 2003, Lewis 1999, Webster 2001, Zhang 2015). However, the variant has also been published on the same allele as another pathogenic variant, p.Met1Val (Eisenberger 2013, Maia-Lopes 2009). The variant is listed in the ClinVar database (Variation ID: 99428) and the dbSNP variant database (rs61750641) with an allele frequency of 0.0615 percent (8/12998 alleles) in the Exome Variant Server and 0.03609 percent (100/277108 alleles) in the Genome Aggregation Database. The amino acid at this position is highly conserved across species, occurs in a transporter domain, and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, this variant is classified as likely pathogenic. This variant would be causative for autosomal recessive Stargardt disease and other ABCA4-related disorders (OMIM#601691). References: Bertelsen M et al. Generalized choriocapillaris dystrophy, a distinct phenotype in the spectrum of ABCA4-associated retinopathies. Invest Ophthalmol Vis Sci. 2014 Apr 29;55(4):2766-76. Cideciyan AV et al. ABCA4-associated retinal degenerations spare structure and function of the human parapapillary retina. Invest Ophthalmol Vis Sci. 2005 Dec;46(12):4739-46. Duncker T et al. Quantitative fundus autofluorescence distinguishes ABCA4-associated and non-ABCA4-associated bull's-eye maculopathy. Ophthalmology. 2015 Feb;122(2):345-55. Eisenberger T et al. Increasing the yield in targeted next-generation sequencing by implicating CNV analysis, non-coding exons and the overall variant load: the example of retinal dystrophies. PLoS One. 2013 Nov 12;8(11):e78496. Jaakson K et al Genotyping microarray (gene chip) for the ABCR (ABCA4) gene. Hum Mutat. 2003 Nov;22(5):395-403. Lewis RA et al. Genotype/Phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease. Am J Hum Genet. 1999 Feb;64(2):422-34. Maia-Lopes S et al. ABCA4 mutations in Portuguese Stargardt patients: identification of new mutations and their phenotypic analysis. Mol Vis. 2009;15:584-91. Webster AR et al. An analysis of allelic variation in the ABCA4 gene. Invest Ophthalmol Vis Sci. 2001 May;42(6):1179-89. Zhang Q et al. Next-generation sequencing-based molecular diagnosis of 35 Hispanic retinitis pigmentosa probands. Sci Rep. 2016 Sep 6;6:32792.
Fulgent Genetics, Fulgent Genetics	RCV000763436	SCV000894203	pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2021-12-15	criteria provided, single submitter	clinical testing
Invitae	RCV000085787	SCV001214008	pathogenic	not provided	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2030 of the ABCA4 protein (p.Arg2030Gln). This variant is present in population databases (rs61750641, gnomAD 0.06%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 22229821, 23143460). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99428). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCA4 protein function. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074874	SCV001240478	pathogenic	Retinal dystrophy	2019-08-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000085787	SCV001247597	pathogenic	not provided	2022-03-01	criteria provided, single submitter	clinical testing	ABCA4: PS1, PM2, PM3, PP3, PS3:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197157	SCV001367793	pathogenic	Age related macular degeneration 2	2018-11-23	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PP2,PP3,PP5.
Revvity Omics, Revvity	RCV000085787	SCV002018125	pathogenic	not provided	2023-06-28	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000178545	SCV002767252	pathogenic	Severe early-childhood-onset retinal dystrophy	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Stargardt disease (MIM #248200), fundus flavimaculatus (MIM #248200), early-onset severe retinal dystrophy (MIM #248200) and retinitis pigmentosa 19 (MIM #601718). (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) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3) (72 heterozygotes, 1 homozygote). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ABC transporter 2 domain (Pfam). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in more than 30 patients with Stargardt disease or ABCA4-related eye disease in the literature where a 2nd disease-causing variant was identified in trans (PMIDs: 30718709; 30670881; 29925512; 28044389; 23953153; 23499370; 18854780; 11379881). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000178545	SCV004045779	pathogenic	Severe early-childhood-onset retinal dystrophy	2023-01-25	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415864	SCV004107331	pathogenic	ABCA4-related condition	2023-06-06	criteria provided, single submitter	clinical testing	The ABCA4 c.6089G>A variant is predicted to result in the amino acid substitution p.Arg2030Gln. This variant has been reported many times as causative for retinal disorders (see for example Lewis et al. 1999. PubMed ID: 9973280; Duncker et al. 2015. PubMed ID: 25283059). This variant is reported in 0.062% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-94471055-C-T). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/99428/). This variant is interpreted as pathogenic.
Retina International	RCV000085787	SCV000117929	not provided	not provided		no assertion provided	not provided
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787516	SCV000926484	pathogenic	Vitreoretinopathy	2018-04-01	no assertion criteria provided	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787517	SCV000926485	pathogenic	Macular dystrophy	2018-04-01	no assertion criteria provided	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787766	SCV000926771	pathogenic	Progressive cone dystrophy (without rod involvement)	2018-04-01	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000085787	SCV001955238	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000085787	SCV001968124	pathogenic	not provided		no assertion criteria provided	clinical testing