ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.6320G>A (p.Arg2107His) (rs62642564)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000085807 SCV000230703 uncertain significance not provided 2015-06-02 criteria provided, single submitter clinical testing
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000408534 SCV000281956 likely pathogenic Stargardt disease 1 2016-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000085807 SCV000321358 pathogenic not provided 2018-12-12 criteria provided, single submitter clinical testing The R2107H variant in the ABCA4 gene has been reported previously in multiple unrelated individuals with Stargardt disease who also harbored a second ABCA4 pathogenic variant (Duncker et al., 2015; Lee et al., 2015; Kellner et al., 2009; Fujinami et al., 2013), suggesting that compound heterozygosity for R2107H and another pathogenic ABCA4 variant results in a phenotype consistent with the spectrum of ABCA4-related disorders. This variant is observed in 488/24024 (2.06%) alleles in individuals of African descent in large population cohorts (Lek et al., 2016). Consistent with this high carrier frequency, R2107H is reported to represent 19.3% of disease-associated alleles in Stargardt patients of African descent (Zernant et al., 2014). Although this variant has been reported in the homozygous state in individuals with Stargardt disease (Zernant et al., 2014; Shroyer et al., 2001), this variant has also been observed in the homozygous state in 5 individuals in large population cohorts (Lek et al., 2016), raising the possibility that homozygosity for R2107H may not associate with disease. The R2107H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Additionally, missense variants in the same codon (R2107C and R2107P) and in nearby residues (D2102E, R2106C) have been reported in the Human Gene Mutation Database in association with Stargardt disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R2107H as a pathogenic variant; however, additional genotype/phenotype studies are needed to better establish its contribution to disease.
Illumina Clinical Services Laboratory,Illumina RCV000391460 SCV000359203 likely benign Macular degeneration 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000291062 SCV000359204 likely benign Retinitis Pigmentosa, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000345905 SCV000359205 likely benign Cone-Rod Dystrophy, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000391457 SCV000359206 likely benign Stargardt Disease, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000085807 SCV001037804 pathogenic not provided 2020-10-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 2107 of the ABCA4 protein (p.Arg2107His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs62642564, ExAC 2.0%), including homozygous individuals, and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individual(s) with Stargardt disease and/or cone dystrophy (PMID: 29925512, 24011517, 19243736, 25283059, 30060493, 28118664, 32307445) and is a commonly reported cause of Stargardt disease in individuals of African-American ancestry (PMID: 25066811). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant (PMID: 9781034, 10458172, 25066811, 28446513, 28559085, 32619608). This variant may be associated with a milder and/or later onset form of Stargardt (PMID: 28446513). ClinVar contains an entry for this variant (Variation ID: 99448). This variant has been reported to affect ABCA4 protein function (PMID: 11017087). This variant disrupts the p.Arg2107 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24097981, 23755871, 29310964, 29925512, 11527935, 30718709). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000408534 SCV001135321 pathogenic Stargardt disease 1 2019-05-28 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001074412 SCV001239994 pathogenic Retinal dystrophy 2019-08-11 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001099680 SCV001256152 likely benign ABCA4-Related Disorders 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000085807 SCV001447776 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287343 SCV001474018 likely pathogenic none provided 2019-10-21 criteria provided, single submitter clinical testing The ABCA4 p.Arg2107His variant accounts for up to 20% of pathogenic variants identified in Stargardt disease patients of African descent (Zernant 2014). This variant has also been identified in trans with other pathogenic alleles (selected references: Rozet 1998, Utz 2013, Jiang 2016, and Fujinami 2019). This variant is found in the African population with an allele frequency of 2% (519/ 24,958 alleles, including 4 homozygotes) in the Genome Aggregation Database. Despite its high population frequency and presence of homozygotes in population databases, only a small number of homozygous individuals with Stargardt disease have been reported in the literature suggesting that in the homozygous state this allele may result in a milder phenotype or reduced penetrance (Zernant 2014). Based on available information, this variant is considered to be likely pathogenic.
Retina International RCV000085807 SCV000117950 not provided not provided no assertion provided not provided
NEI Ophthalmic Genomics Laboratory,National Institutes of Health RCV000085807 SCV000119181 not provided not provided no assertion provided not provided
NIHR Bioresource Rare Diseases, University of Cambridge RCV000408534 SCV000599013 likely pathogenic Stargardt disease 1 2015-01-01 no assertion criteria provided research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000505080 SCV000599014 likely pathogenic Macular dystrophy 2015-01-01 no assertion criteria provided research

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