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

gnomAD frequency: 0.00654  dbSNP: rs62642564

Total submissions: 23

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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085807	SCV001037804	pathogenic	not provided	2025-01-27	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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, Medical Genetics	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	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	ABCA4: PM3:Very Strong, PM1, PM5, PM2:Supporting, PS3:Supporting, BS2
Dept Of Ophthalmology, Nagoya University	RCV001074412	SCV004705685	pathogenic	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000408534	SCV004806922	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2024-10-07	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017398	SCV004847331	likely pathogenic	Stargardt disease	2023-10-02	criteria provided, single submitter	clinical testing	The p.Arg2107His variant in ABCA4 has been reported in the compound heterozygous state in at least 19 individuals and in the homozygote state in an individual with clinical features of Stargardt disease. The homozygous individual had late-onset disease (Rozet 1998 PMID: 9781034, Utz 2013 PMID: 24011517, Zernant 2014 PMID: 25066811, Stone 2017 PMID: 28559085, Vallim Salles 2018 PMID: 30093795) and accounts for about 1/5 of pathogenic variants identified in affected individuals of African American descent (Zernant 2014 PMID: 25066811). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 99448) and has been identified in 2.1% (864/41452) of African chromosomes by gnomAD including 9 homozygotes (http://gnomad.broadinstitute.org, v.3.1.2), which is higher than the expected frequency for penetrant disease-causing alleles. However, very few homozygous individuals with Stargardt disease have been reported in the literature suggesting that in the homozygous state, this allele may result in a milder, subclinical phenotype or reduced penetrance. In vitro studies show that this variant showed slightly reduced expression in transfected cells and decreased ATPase activity but were still able to bind and be stimulated by trans-retinal (Curtis 2020 PMID: 32845050), which could be consistent with the milder phenotype observed in homozygotes and the later age of onset of disease. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Stargardt disease and is expected to cause more severe disease in the compound heterozygote state with a penetrant, more severe pathogenic variant on the other copy of the gene (in trans). ACMG/AMP Criteria applied: PM3_VeryStrong, PP3.
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004815130	SCV005070748	likely pathogenic	Optic atrophy	2022-01-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001074412	SCV005073472	likely pathogenic	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000408534	SCV005417603	pathogenic	Severe early-childhood-onset retinal dystrophy		criteria provided, single submitter	clinical testing	PP3_Moderate+PM3_VeryStrong+PP4
Fulgent Genetics, Fulgent Genetics	RCV005025167	SCV005656861	pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2024-01-20	criteria provided, single submitter	clinical testing
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
PreventionGenetics, part of Exact Sciences	RCV004528786	SCV004111341	likely pathogenic	ABCA4-related disorder	2024-03-05	no assertion criteria provided	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. 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.
Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	RCV000408534	SCV005049497	likely pathogenic	Severe early-childhood-onset retinal dystrophy		no assertion criteria provided	research