ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.5693G>A (p.Arg1898His) (rs1800552)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000408593 SCV000281934 likely pathogenic Stargardt disease 1 2016-01-01 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000085752 SCV000608476 uncertain significance not provided 2020-07-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000623966 SCV000742854 uncertain significance Inborn genetic diseases 2014-10-14 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000085752 SCV000855135 uncertain significance not provided 2018-03-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778998 SCV000915439 pathogenic ABCA4-Related Disorders 2018-09-18 criteria provided, single submitter clinical testing The ABCA4 c.5693G>A (p.Arg1898His) missense variant has been reported in at least eight studies in which it was found in 18 individuals with Stargardt disease, including six compound heterozygotes, two heterozygotes, four who carried the variant in a complex allele, and six in whom zygosity information is not provided, and in a compound heterozygous state in one proband with cone-rod dystrophy (Allikmets et al. 1997a; Lewis et al. 1999; Rivera et al. 2000; Ernest et al. 2009; Anastasakis et al. 2011; Duno et al. 2012; Westeneng-van Haaften et al. 2012; Fujinami et al. 2013). The p.Arg1898His variant was identified in a heterozygous state in one of 880 control chromosomes (Allikmets et al. 1997a; Lewis et al. 1999; Rivera et al. 2000) and is reported at a frequency of 0.00281 in the European (non-Finnish) population of the Exome Aggregation Consortium. Westeneng-van Haaften et al. (2012) predicted a decreased protein yield in the presence of the variant and suggested the variant may have a mild effect; however, two other studies did not observe a difference compared to wild type (Allikmets et al. 1997b; Sun et al. 2000). Based on the collective evidence, the p.Arg1898His 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.
Invitae RCV000085752 SCV001047969 likely benign not provided 2020-12-04 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001075015 SCV001240625 uncertain significance Retinal dystrophy 2018-02-14 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196150 SCV001366671 uncertain significance Age-related macular degeneration 2 2019-04-09 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PP5.
GeneDx RCV000085752 SCV001772092 uncertain significance not provided 2021-01-23 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Identified in patients with ABCA4-related retinal dystrophies in published literature, however, R1898H has been reported on the same allele (in cis) with other pathogenic variants in the ABCA4 gene (Allikmets et al., 1997; Oh et al., 2004; Westeneng-van Haaften et al., 2012; Lewis et al., 1999; Fujinami et al., 2013); In vitro functional studies demonstrate that the R1898H variant results in ATPase activity that is indistinguishable from wild type and has minimal effect on the structure and function of the protein (Sun et al., 2000; Garces et al., 2020); This variant is associated with the following publications: (PMID: 22449572, 9295268, 33375396, 31884623, 31456290, 28559085, 30718709, 29925512, 29207047, 29555955, 10958763, 11017087, 25087612, 9973280, 22229821, 20029649, 28118664, 21293320, 9054934, 23953153, 15579991)
Retina International RCV000085752 SCV000117893 not provided not provided no assertion provided not provided
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787513 SCV000926480 likely pathogenic Stargardt disease 2018-04-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787764 SCV000926769 likely pathogenic Retinitis pigmentosa 2018-04-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000085752 SCV001553374 uncertain significance not provided no assertion criteria provided clinical testing The ABCA4 p.R1898H variant was identified in the literature as a heterozygous, compound heterozygous, or complex variant in >20 individuals with age-related macular degeneration, Stargardt Disease, atypical maculopathy or bilateral severe familial exudative vitreoretinopath (Allikmets_1997_PMID:9295268; Rivera_2000_PMID:10958763; Anastasakis _2011_PMID:21293320; Duno_2012_PMID:22229821; Fujinami_2013_PMID:23953153; Lin_2018_PMID:29207047; Westeneng-van Haaften_2012_PMID:22449572). However, this variant has been reported in an individual with Stargardt-flavimaculatus who also carried two likely pathogenic variants in the ABCA4 gene (Duno_2012_PMID:22229821). The variant was identified in dbSNP (ID: rs1800552) and in ClinVar (classified as uncertain significance by Ambry Genetics, EGL Genetics and three other laboratories; as likely benign by Invitae; as likely pathogenic by Institute of Human Genetics, Univ. Regensburg and Medical Genetics Laboratory, Kennedy Center, Juliane Marie Center, Rigshospitalet; and as pathogenic by Illumina). The variant was identified in control databases in 438 of 282700 chromosomes at a frequency of 0.001549, and was observed at the highest frequency in the European (non-Finnish) population in 324 of 129094 chromosomes (freq: 0.002510) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.R1898 residue is not conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; however this information is not predictive enough to rule out pathogenicity. Functional ATPase assays have demonstrated that the p.R1898H variant displays ATPase activity comparable to wild type (Sun_2000_PMID:11017087). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) 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 RCV000085752 SCV001921177 uncertain significance not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000085752 SCV001953417 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000085752 SCV001976099 uncertain significance not provided no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000085752 SCV001978734 uncertain significance not provided no assertion criteria provided clinical testing

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