Submissions for variant NM_000350.3(ABCA4):c.6089G>A (p.Arg2030Gln) (rs61750641)

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	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	Stargardt disease 1	2016-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000085787	SCV000329050	pathogenic	not provided	2017-06-02	criteria provided, single submitter	clinical testing	The R2030Q variant has been published previously in association with ABCA4-related disorders (Lewis et al., 1999; Yatsenko et al., 2001; Briggs et al., 2001). The variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R2030Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position within the critical ABC transporter 2 domain that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (L2027F, H2032R, L2033R, L2035P) have been reported in the Human Gene Mutation Database in association with ABCA4-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we consider this variant to be pathogenic.
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	likely 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
Invitae	RCV000085787	SCV001214008	pathogenic	not provided	2020-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 2030 of the ABCA4 protein (p.Arg2030Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs61750641, ExAC 0.06%). This variant has been observed on the opposite chromosome (in trans) from other pathogenic variants in individuals affected with Stargardt disease (PMID: 23143460, 22229821). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 99428, 236068). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 Praxis fuer Humangenetik Tuebingen	RCV000085787	SCV001247597	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV001197157	SCV001367793	pathogenic	Pigmentary retinopathy; Central scotoma; Macular degeneration; Blurred vision	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: PS1,PS3,PP2. This variant was detected in heterozygous state.
Retina International	RCV000085787	SCV000117929	not provided	not provided		no assertion provided	not provided
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet	RCV000787516	SCV000926484	pathogenic	Vitreoretinopathy	2018-04-01	no assertion criteria provided	research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet	RCV000787517	SCV000926485	pathogenic	Macular dystrophy	2018-04-01	no assertion criteria provided	research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet	RCV000787766	SCV000926771	pathogenic	Progressive cone dystrophy (without rod involvement)	2018-04-01	no assertion criteria provided	research