ClinVar Miner

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

gnomAD frequency: 0.00189  dbSNP: rs56357060
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000085627 SCV000228691 uncertain significance not provided 2015-02-15 criteria provided, single submitter clinical testing
Illumina Laboratory Services, 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 RCV000085627 SCV001157693 uncertain significance not provided 2019-09-04 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 2001). 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 Center for Human Genetics Tuebingen RCV000085627 SCV001248247 uncertain significance not provided 2023-04-01 criteria provided, single submitter clinical testing ABCA4: PM1
Invitae RCV000085627 SCV001600164 likely benign not provided 2024-01-31 criteria provided, single submitter clinical testing
GeneDx RCV000085627 SCV002757194 uncertain significance not provided 2022-11-26 criteria provided, single submitter clinical testing Observed in patients with Stargardt disease in published literature who were reported to have V1433I on the same allele (in cis) with other ABCA4 variants or seen phase unknown with two other pathogenic ABCA4 variants, therefore questioning the pathogenicity of V1433I (Klevering et al., 2004; Lambertus et al., 2016; Murro et al., 2017; Birtel et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22995991, 34073554, 22025579, 27527345, 28002570, 28430335, 34426522, 20981092, 35119454, 29555955, 33090715, 15494742, 28341476, 32037395, 24409374, 22264887, 9973280)
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
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg RCV000408575 SCV000281885 likely pathogenic Severe early-childhood-onset retinal dystrophy 2016-01-01 flagged submission clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000085627 SCV001548668 uncertain significance not provided no assertion criteria provided clinical testing The ABCA4 p.Val1433Ile variant was identified in 9 of 1492 proband chromosomes (frequency: 0.006) from individuals or families with stargardt disease, cone-rod dystrophy, age-related macular degeneration and retinitis pigmentosa (Schulz_2017_PMID:28118664; Thiadens_2012_PMID:22264887; Aguirre-Lamban_2009_PMID:19028736; Baum_2003_PMID:12592048; Lewis_1999_PMID:9973280). The variant was identified in dbSNP (ID: rs56357060), ClinVar (classified as likely pathogenic by Institute of Human Genetics, Univ. Regensburg and as a VUS by EGL Genetic Diagnostics and Illumina) and in LOVD 3.0 (classified as pathogenic once, a VUS four times and likely benign twice). The variant was also identified in control databases in 470 of 282886 chromosomes (1 homozygous) at a frequency of 0.001661 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 322 of 129192 chromosomes (freq: 0.002492), Other in 14 of 7226 chromosomes (freq: 0.001937), East Asian in 35 of 19952 chromosomes (freq: 0.001754), Latino in 56 of 35440 chromosomes (freq: 0.00158), European (Finnish) in 19 of 25118 chromosomes (freq: 0.000756), African in 16 of 24972 chromosomes (freq: 0.000641), South Asian in 7 of 30616 chromosomes (freq: 0.000229), and Ashkenazi Jewish in 1 of 10370 chromosomes (freq: 0.000096). The p.Val1433 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Clinical Genetics, Academic Medical Center RCV000085627 SCV001922759 uncertain significance not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000085627 SCV001951445 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000085627 SCV002038195 uncertain significance not provided no assertion criteria provided clinical testing

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