Total submissions: 15
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Institute of Human Genetics, |
RCV000408534 | SCV000281956 | likely pathogenic | Severe early-childhood-onset retinal dystrophy | 2016-01-01 | criteria provided, single submitter | clinical testing | |
Gene |
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, |
RCV000085807 | SCV001447776 | likely pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
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. |
Ce |
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, |
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, |
RCV000085807 | SCV000119181 | not provided | not provided | no assertion provided | not provided | ||
Eurofins Ntd Llc |
RCV000085807 | SCV000230703 | uncertain significance | not provided | 2015-06-02 | flagged submission | clinical testing | |
NIHR Bioresource Rare Diseases, |
RCV000408534 | SCV000599013 | likely pathogenic | Severe early-childhood-onset retinal dystrophy | 2015-01-01 | no assertion criteria provided | research | |
NIHR Bioresource Rare Diseases, |
RCV000505080 | SCV000599014 | likely pathogenic | Macular dystrophy | 2015-01-01 | no assertion criteria provided | research |