ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.4297G>A (p.Val1433Ile) (rs56357060)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000085627 SCV000228691 uncertain significance not provided 2015-02-15 criteria provided, single submitter clinical testing
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000408575 SCV000281885 likely pathogenic Stargardt disease 1 2016-01-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778256 SCV000914428 uncertain significance ABCA4-Related Disorders 2017-04-27 criteria provided, single submitter clinical testing The ABCA4 c.4297G>A (p.Val1433Ile) missense variant has been reported in 14 studies in individuals with a range of ocular disorders (Lewis et al. 1999; Souied et al. 2000; Webster et al. 2001; Baum et al. 2003; Klevering et al. 2004; Valverde et al. 2007; Michaelides et al. 2007; Aguirre-Lamban et al. 2009; Kellner et al. 2009; Passerini et al. 2010; Song et al. 2011; Verdina et al. 2012; Huang et al. 2014; Grassmann et al. 2015). The p.Val1433Ile variant was found in a homozygous state in two individuals with Stargardt disease (STGD), in a compound heterozygous state in one individual with STGD and one with retinal degeneration. The variant was further reported in a complex compound heterozygous state in a patient with recessive cone-rod dystrophy (CRD), and in a heterozygous state in four patients with recessive CRD, three patients with age-related macular degeneration (AMD), and one patient each with STGD and bull’s eye maculopathy. Segregation analysis in one AMD family revealed that the variant did not segregate with disease. The variant was found in a heterozygous state in two of 484 controls and is reported at a frequency of 0.00441 in the Other population of the Exome Aggregation Consortium. Additionally, one homozygote is reported in the European (non-Finnish) population of the Exome Aggregation Consortium. Despite the evidence of causality, the discordant reports of lack of co-segregation of the variant with disease and the presence of an ostensibly healthy homozygote in the frequency databases present conflicting support for pathogenicity. The p.Val1433Ile variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000665 SCV001157693 uncertain significance not specified 2018-12-12 criteria provided, single submitter clinical testing The ABCA4 variant c.4297G>A; p.Val1433Ile (rs56357060) is reported in the medical literature in individuals with ABCA4-related disease as well as age related macular degeneration in the compound heterozygous state in a few individuals, but often without an additional pathogenic variant (Aguirre-Lamban 2009, Klevering 2004, Lewis 1999, Michaelides 2007, Song 2011, Souied 2000, Taylor 2017, Thiadens 2012, Webster ). The variant is reported in the ClinVar database (Variation ID: 99274) and in the Genome Aggregation Database in the general population with an allele frequency of 0.2% (470/282886 alleles including 1 homozygote). The amino acid at this position is highly conserved but computational algorithms (PolyPhen-2, SIFT) predict this variant is tolerated. Considering available information, there is insufficient evidence to classify this variant with certainty. References: Aguirre-Lamban J et al. Molecular analysis of the ABCA4 gene for reliable detection of allelic variations in Spanish patients: identification of 21 novel variants. Br J Ophthalmol. 2009 May;93(5):614-21. Klevering BJ et al. Three families displaying the combination of Stargardt's disease with cone-rod dystrophy or retinitis pigmentosa. Ophthalmology. 2004 Mar;111(3):546-53. 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. Michaelides M et al. ABCA4 mutations and discordant ABCA4 alleles in patients and siblings with bull's-eye maculopathy. Br J Ophthalmol. 2007 Dec;91(12):1650-5. Song J et al. High-throughput retina-array for screening 93 genes involved in inherited retinal dystrophy. Invest Ophthalmol Vis Sci. 2011 Nov 25;52(12):9053-60. Souied EH et al. ABCR gene analysis in familial exudative age-related macular degeneration. Invest Ophthalmol Vis Sci. 2000 Jan;41(1):244-7. Taylor RL et al. Panel-Based Clinical Genetic Testing in 85 Children with Inherited Retinal Disease. Ophthalmology. 2017 Jul;124(7):985-991. Thiadens AA et al. Clinical course, genetic etiology, and visual outcome in cone and cone-rod dystrophy. Ophthalmology. 2012 Apr;119(4):819-26 Webster AR et al. An analysis of allelic variation in the ABCA4 gene. Invest Ophthalmol Vis Sci. 2001 May;42(6):1179-89.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000085627 SCV001248247 uncertain significance not provided 2020-05-01 criteria provided, single submitter clinical testing
Retina International RCV000085627 SCV000117766 not provided not provided no assertion provided not provided
NEI Ophthalmic Genomics Laboratory,National Institutes of Health RCV000085627 SCV000119178 not provided not provided no assertion provided not provided

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