ClinVar Miner

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

gnomAD frequency: 0.00654  dbSNP: rs62642564
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 15
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg RCV000408534 SCV000281956 likely pathogenic Severe early-childhood-onset retinal dystrophy 2016-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000085807 SCV000321358 pathogenic not provided 2022-03-18 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Additional genotype/phenotype studies are needed to better establish the contribution of R2107H to disease; This variant is associated with the following publications: (PMID: 16123440, 23499370, 25444351, 26780318, 23982839, 28559085, 16917483, 11385708, 19230850, 14709597, 15223829, 25884411, 26214332, 26311262, 19365039, 23882696, 25066811, 24011517, 11384574, 25283059, 25910913, 19243736, 23953153, 9781034, 29555955, 30093795, 29925512, 32845050, 32581362, 22995991, 22025579, 33301772, 33691693, 34426522, 32619608, 33261146, 22264887, 34073554)
Invitae RCV000085807 SCV001037804 pathogenic not provided 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2107 of the ABCA4 protein (p.Arg2107His). This variant is present in population databases (rs62642564, gnomAD 2.1%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with Stargardt disease and/or cone dystrophy (PMID: 9781034, 10458172, 19243736, 24011517, 25066811, 25283059, 28118664, 28446513, 28559085, 29925512, 30060493, 32307445, 32619608). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99448). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCA4 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: 11527935, 23755871, 24097981, 29310964, 29925512, 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 Severe early-childhood-onset retinal dystrophy 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
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 RCV000085807 SCV001474018 likely pathogenic not provided 2023-11-29 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.
3billion RCV000408534 SCV002058581 pathogenic Severe early-childhood-onset retinal dystrophy 2022-01-03 criteria provided, single submitter clinical testing The same variant was previously reported several times in trans with another pathogenic variant in this gene (PMID: 9781034, 10458172, 25066811, 28446513, 28559085, 32619608) (PM3_VS). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000635988, PMID:11527935,18977788, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.88, 3CNET: 0.987, PP3_P). A missense variant is a common mechanism associated with Stargardt disease 1 (PP2_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
CeGaT Center for Human Genetics Tuebingen RCV000085807 SCV004009857 likely pathogenic not provided 2023-06-01 criteria provided, single submitter clinical testing ABCA4: PM3:Very Strong, PM5, PM2:Supporting, PS3:Supporting, BS2
Preventiongenetics, part of Exact Sciences RCV003390786 SCV004111341 likely pathogenic ABCA4-related condition 2023-03-12 criteria provided, single submitter clinical testing The ABCA4 c.6320G>A variant is predicted to result in the amino acid substitution p.Arg2107His. This variant has been reported many times to be causative for ABCA4-associated retinal disorders (see for example Rozet et al. 1998. PubMed ID: 9781034; Riveiro-Alvarez et al. 2009. PubMed ID: 18977788; Fujinami et al. 2018. PubMed ID: 29925512). This variant has been documented in 2.1% of alleles in individuals of African descent in gnomAD, including multiple homozygous individuals (http://gnomad.broadinstitute.org/variant/1-94466624-C-T). While this allele frequency is higher than expected for most pathogenic variants, it has been reported that the carrier frequency for late-onset Stargardt disease is particularly high in the general population (Riveiro-Alvarez et al. 2009. PubMed ID: 18977788). Missense prediction programs classify this amino acid change as damaging, and multiple functional studies have confirmed that this variant has a mild hypomorphic effect on the protein (Sun et al. 2000. PubMed ID: 11017087; Curtis et al. 2020. PubMed ID: 32845050). Given the mild effect, the literature suggests that individuals who are homozygous for this variant have a very mild phenotype (Zernant et al. 2014. PubMed ID: 25066811). In summary, we interpret this variant as 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
Eurofins Ntd Llc (ga) RCV000085807 SCV000230703 uncertain significance not provided 2015-06-02 flagged submission clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV000408534 SCV000599013 likely pathogenic Severe early-childhood-onset retinal dystrophy 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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.