ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.4328G>A (p.Arg1443His) (rs61750142)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000408447 SCV000281886 likely pathogenic Stargardt disease 1 2016-01-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000779005 SCV000915446 pathogenic ABCA4-Related Disorders 2019-01-12 criteria provided, single submitter clinical testing Across a selection of the literature, the ABCA4 c.4328G>A (p.Arg1443His) missense variant has been reported in a compound heterozygous state in at least five individuals, including four affected with Stargardt disease, one described as affected with ABCA4-associated disease and one with ABCA4-associated retinopathies (Rivera et al. 2000; Testa et al. 2012; Chacón-Camacho et al. 2013; Fujinami et al. 2013; Nõupuu et al. 2014; Schulz et al. 2017). In addition Roberts et al. (2011) identified the p.Arg1443His variant in one patient allele from a cohort of 181 individuals with ABCA4-associated retinopathies. The variant was absent from 220 control individuals and is reported at a frequency of 0.000045 in the European (non-Finnish) population of the Exome Aggregation Consortium. The Arg1443 residue is noted to be well conserved. Biswas-Fiss et al. (2010) compared the ABCA4 wild type structure with that of three variant structures, including the p.Arg1443His variant using CD spectral analysis. The p.Arg1443His variant structure was shown to be significantly altered with loss of alpha-helical secondary structure. The same study also demonstrated decreased binding affinity to its substrate. Based on the collective evidence, the p.Arg1443His 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.
Blueprint Genetics RCV001073587 SCV001239138 pathogenic Retinal dystrophy 2019-07-06 criteria provided, single submitter clinical testing
Invitae RCV000085631 SCV001418752 pathogenic not provided 2019-10-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1443 of the ABCA4 protein (p.Arg1443His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs61750142, ExAC 0.004%). This variant has been observed in several individuals affected with autosomal recessive Stargardt disease (PMID: 15161829, 22661472, 23419329, 23982839, 28118664, 29925512). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99278). This variant has been reported to affect ABCA4 protein function (PMID: 20404325). For these reasons, this variant has been classified as Pathogenic.
Retina International RCV000085631 SCV000117770 not provided not provided no assertion provided not provided

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