ClinVar Miner

Submissions for variant NM_000350.2(ABCA4):c.5882G>A (rs1800553)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 39
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000078670 SCV000110529 pathogenic not provided 2016-11-30 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000787514 SCV000221171 pathogenic Stargardt disease 2020-05-28 criteria provided, single submitter clinical testing The p.Gly1961Glu (NM_000350.2 c.5882G>A) variant in ABCA4 has been reported >20 individuals with Stargardt disease and other retinal phenotypes and segregated with disease in 5 affected individuals from 5 families, but has been associated with reduced penetrance (Allikmets 1997 PMID:9295268, Burke 2012 PMID:22312191, Burke 2012 PMID:22661473, Song 2011 PMID:22025579, Burke 2010 PMID:20696155, Wiszniewski 2005 PMID:16103129, Cella 2009 PMID:19217903, Cideciyan 2009 PMID: 19074458). The variant shows a statistically significant (p<0.0001) difference in allele frequency in cases (5%) compared to the general population (0.4%, http://gnomad.broadinstitute.org). In vitro functional studies support an impact on protein function (Sun 2000 PMID:11017087). This variant has also been reported as Pathogenic by multiple clinical labs in ClinVar (Variation ID 7879). In summary, this variant meets criteria to be classified as pathogenic for Stargardt disease in an autosomal recessive manner, though it may show reduced penetrance and a milder clinical presentation compared to other pathogenic variants in the ABCA4 gene. ACMG/AMP Criteria applied: PS3_Supporting, PM3_VeryStrong, PP1_Strong.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000008340 SCV000267674 likely pathogenic Stargardt disease 1 criteria provided, single submitter research identified in compound heterozygous state in affected individual/s with macular isease
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000008340 SCV000281939 pathogenic Stargardt disease 1 2016-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000078670 SCV000321357 pathogenic not provided 2018-07-16 criteria provided, single submitter clinical testing The G1961E variant in the ABCA4 gene has been reported previously in association with Stargardt disease, cone-rod dystrophy, and age-related macular degeneration (Rivera et al., 2000; Klevering et al., 2005; Alapati et al., 2014). Additionally, it is reported as pathogenic in ClinVar by different clinical laboratories, but additional evidence is not available (ClinVar Variant ID: 7888; Landrum et al., 2016). Individuals homozygous for G1961E showed a range of retinal abnormalities but typically had milder, late-onset Stargardt disease, while severe presentations were linked to the presence of additional ABCA4 variants (Burke et al., 2012). The G1961E variant was also observed in 613/121,302 (0.5%) alleles, including 4 homozygous individuals, in large population cohorts (Lek et al., 2016), which is consistent with its milder presentation. The G1961E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Functional studies demonstrated that this variant results in reduced ATPase activity (Sun et al., 2000). In summary, we interpret G1961E as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000273328 SCV000359235 pathogenic ABCA4-Related Disorders 2017-05-08 criteria provided, single submitter clinical testing The ABCA4 c.5882G>A (p.Gly1961Glu) missense variant has been reported in at least eight studies in which it is found in over 50 individuals, 54 of whom were diagnosed with Stargardt disease, including 18 who carry the variant in a homozygous state, in at least 26 who carry the variant in a compound heterozygous state, and in seven who carry the variant in a heterozygous state. The p.Gly1961Glu variant is also found in a heterozygous state in two asymptomatic individuals (Allikmets et al. 1997; Wiszniewski et al. 2005; Kitiratschky et al. 2008; Cella et al. 2009; Burke et al. 2012; Burke et al. 2012; Fujinami et al. 2013; Lee et al. 2016). The p.Gly1961Glu variant is associated with a mild phenotype. Fifteen of the individuals carrying the variant exhibited bull's eye maculopathy and retinal dysfunction limited to the macula and not typical general dysfunction (Cella et al. 2009). Six individuals were found to carry additional variants in the ABCA4 gene and exhibited a more severe phenotype (Burke et al. 2012). The p.Gly1961Glu variant was absent from 220 control individuals and is reported at a frequency of 0.01498 in the South Asian population of the Exome Aggregation Consortium. Haplotype analysis in the South Asian population suggested that the p.Gly1961Glu variant has a founder effect in this population (Fujinami et al. 2013). Functional studies demonstrated that the p.Gly1961Glu variant protein resulted in reduced ATPase activity and ATP binding, while maintaining expression levels comparable to wild type, which is consistent with a mild phenotype. Additionally, the variant protein ATPase activity was inhibited by all-trans retinal, in contrast to the stimulation seen in wild type (Sun et al. 2000; Burke et al 2012a). Based on the collective evidence, the p.Gly1961Glu 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.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000008340 SCV000494247 pathogenic Stargardt disease 1 2016-06-28 criteria provided, single submitter clinical testing The c.5882G>A (p.Gly1961Glu) missense variant in the ABCA4 gene has been previously reported in multiple individuals affected with Stargardt Disease (Kousal et al., 2014; Fritsche et al., 2012; Burke et al., 2012; Cella et al., 2009). This variant was observed at a significantly higher frequency in affected individuals than in a control population (OR=41.03 (5.4-310.1)). Furthermore, this variant is predicted to lie within a nucleotide binding domain, and in vitro functional assays demonstrated that this variant resulted in decreased ATP-binding capacity and ATP hydrolysis, despite an increase of the total amount of ABCA4 protein (Sun et al., 2000). Multiple in silico algorithms predict this variant to have a deleterious effect (GERP=5.35; CADD = 23.6; PolyPhen = 1.0; SIFT = 0.0). Emory Genetics Laboratory has classified this variant as Pathogenic. Therefore, this collective evidence supports the classification of the c.5882G>A (p.Gly1961Glu) as a Pathogenic variant for Stargardt Disease. We have confirmed this finding in our laboratory using Sanger sequencing.
Ambry Genetics RCV000624210 SCV000741007 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000008340 SCV000891470 likely pathogenic Stargardt disease 1 2017-12-30 criteria provided, single submitter curation
Mendelics RCV000008340 SCV001135328 likely pathogenic Stargardt disease 1 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001680 SCV001159230 pathogenic none provided 2020-02-20 criteria provided, single submitter clinical testing "The ABCA4 c.5882G>A; p.Gly1961Glu variant (rs1800553) has been reported in the medical literature in both the homozygous and compound heterozygous state in many individuals with ABCA4-related diseases (Allikmets 1997, Cella 2009, Garces 2018, Salles 2017, Wiszniewski 2005). Studies on individuals homozygous for this variant indicate that it is most often associated with milder, later onset retinal disease (Burke 2012). The variant is described as pathogenic or likely pathogenic by several sources in the ClinVar database (Variation ID: 7888). The variant is also described as one of the most common pathogenic variant in Stargardt patients (Burke 2012) and is found in the general population with an overall allele frequency of 0.5% (1291/282848 alleles, including 10 homozygotes) and an allele frequency of 1.4% (422/30614 alleles) in the South Asian population in the Genome Aggregation Database. The glycine at this position is highly conserved and computational algorithms predict this variant is deleterious. In support of this prediction, functional studies show this variant lies in a critical functional domain and results in reduced function of this variant protein compared to the wild type protein (Garces 2018, Sun 2000). Considering available information, this variant is classified as pathogenic but may result in a milder clinical phenotype. References: Allikmets R et al. Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science. 1997 Sep 19;277(5333):1805-7. Burke TR et al. Retinal phenotypes in patients homozygous for the G1961E mutation in the ABCA4 gene. Invest Ophthalmol Vis Sci. 2012 Jul 3;53(8):4458-67. Cella W et al. G1961E mutant allele in the Stargardt disease gene ABCA4 causes bull's eye maculopathy. Exp Eye Res. 2009 Jun 15;89(1):16-24 Garces F et al. Correlating the Expression and Functional Activity of ABCA4 Disease Variants With the Phenotype of Patients With Stargardt Disease. Invest Ophthalmol Vis Sci. 2018 May 1;59(6):2305-2315. Salles MV et al. Novel Complex ABCA4 Alleles in Brazilian Patients With Stargardt Disease: Genotype-Phenotype Correlation. Invest Ophthalmol Vis Sci. 2017 Nov 1;58(13):5723-5730 Sun H et al. Biochemical defects in ABCR protein variants associated with human retinopathies. Nat Genet. 2000 Oct;26(2):242-6. Wiszniewski W et al. ABCA4 mutations causing mislocalization are found frequently in patients with severe retinal dystrophies. Hum Mol Genet. 2005 Oct 1;14(19):2769-78
Invitae RCV000078670 SCV001229561 pathogenic not provided 2020-10-25 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 1961 of the ABCA4 protein (p.Gly1961Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs1800553, ExAC 1.5%), including several homozygous individuals, and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in many individuals with autosomal recessive Stargardt disease, and has been found in trans (on the opposite chromosome) from many different pathogenic variants (PMID: 28559085, 28181551, 30060493, 19074458, 29555955). This variant appears to be significantly enriched in individuals with Stargardt compared to the general population (PMID: 28327576). In addition, in a large meta-analysis, this variant conferred a 3.2-fold increased risk (95% CI: 1.74–5.95) for age-related macular degeneration (PMID: 25921964). This variant appears to be associated with milder and/or later onset disease (PMID: 28327576, 28446513). ClinVar contains an entry for this variant (Variation ID: 7888). This variant has been reported to affect ABCA4 protein function (PMID: 11017087, 29847635). In summary, this variant is reported to cause disease. However, because this variant is associated with a milder form of disease than other pathogenic alleles in the ABCA4 gene, and because it is found in homozygosity in healthy individuals, it has been classified as Pathogenic (low penetrance).
Blueprint Genetics RCV000505149 SCV001240512 pathogenic Retinal dystrophy 2019-08-17 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000078670 SCV001247601 pathogenic not provided 2021-06-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000678513 SCV001367829 likely pathogenic Age-related macular degeneration 2 2019-09-05 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: Pm1,PM5,PP3,PP5.
Hadassah Hebrew University Medical Center RCV001254602 SCV001430593 likely pathogenic Cone-rod dystrophy 3; Stargardt disease 1; Retinitis pigmentosa 19 2019-06-20 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV001258239 SCV001435147 uncertain significance Joubert syndrome 5 criteria provided, single submitter research The homozygous p.Gly1961Glu variant in ABCA4 has been identified in at least 12 individuals with age related macular degeneration (PMID: 22661473), but has also been identified in >1% of South Asian chromosomes and 4 homozygotes by ExAC (http://gnomad.broadinstitute.org/). This variant also cosegregates with disease in families and is only rarely found in cis (PMID: 22661473). In vitro functional studies provide some evidence that the p.Gly1961Glu variant may slightly impact protein function (PMID: 22661473). However, these types of assays may not accurately represent biological function. In summary, the clinical significance of this variant is uncertain.
Institute of Human Genetics, University of Leipzig Medical Center RCV000008341 SCV001440307 pathogenic Cone-rod dystrophy 3 2019-01-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000078670 SCV001447556 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000078670 SCV001448817 pathogenic not provided 2018-12-24 criteria provided, single submitter clinical testing
Baylor Genetics RCV000008340 SCV001521357 pathogenic Stargardt disease 1 2020-01-17 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Institute of Medical Molecular Genetics, University of Zurich RCV000008340 SCV001548126 likely pathogenic Stargardt disease 1 2021-01-30 criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV000008341 SCV001573158 pathogenic Cone-rod dystrophy 3 2021-04-14 criteria provided, single submitter clinical testing This ABCA4 variant (rs1800553) is among the most frequent retinal dystrophy-associated variants with an allele frequency of ~1.4% in South Asians. It has an entry in ClinVar. Individuals homozygous for p.Gly1961Glu show a range of retinal abnormalities but typically have a milder clinical presentation than individuals with additional ABCA4 variants on the opposite chromosome. This variant is located within a nucleotide binding domain of ABCA4, and functional studies demonstrate that this variant results in reduced ATPase activity9,10. This variant alone is not expected to cause CORD3. We consider c.5882G>A to be pathogenic.
Genomics England Pilot Project,Genomics England RCV000678513 SCV001760045 pathogenic Age-related macular degeneration 2 criteria provided, single submitter clinical testing
Genomics England Pilot Project,Genomics England RCV001542557 SCV001760046 pathogenic Retinitis pigmentosa 19 criteria provided, single submitter clinical testing
OMIM RCV000008339 SCV000028547 risk factor MACULAR DEGENERATION, AGE-RELATED, 2, SUSCEPTIBILITY TO 2008-07-01 no assertion criteria provided literature only
OMIM RCV000008340 SCV000028548 pathogenic Stargardt disease 1 2008-07-01 no assertion criteria provided literature only
OMIM RCV000008341 SCV000028549 pathogenic Cone-rod dystrophy 3 2008-07-01 no assertion criteria provided literature only
Retina International RCV000078670 SCV000117911 not provided not provided no assertion provided not provided
NEI Ophthalmic Genomics Laboratory,National Institutes of Health RCV000078670 SCV000119180 not provided not provided no assertion provided not provided
Division of Human Genetics,Children's Hospital of Philadelphia RCV000008341 SCV000536764 pathogenic Cone-rod dystrophy 3 2016-06-10 no assertion criteria provided research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504952 SCV000599002 likely pathogenic Macular dystrophy 2015-01-01 no assertion criteria provided research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000505149 SCV000599003 likely pathogenic Retinal dystrophy 2015-01-01 no assertion criteria provided research
GenomeConnect, ClinGen RCV000008340 SCV000607275 not provided Stargardt disease 1 no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Human Genetics - Radboudumc,Radboudumc RCV000678513 SCV000804584 pathogenic Age-related macular degeneration 2 2016-09-01 no assertion criteria provided clinical testing
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787514 SCV000926482 pathogenic Stargardt disease 2018-04-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000504952 SCV000926781 likely pathogenic Macular dystrophy 2018-04-01 no assertion criteria provided research
Sharon lab,Hadassah-Hebrew University Medical Center RCV000787514 SCV001160823 pathogenic Stargardt disease 2019-06-23 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000078670 SCV001549384 pathogenic not provided no assertion criteria provided clinical testing The ABCA4 p.Gly1961Glu variant was identified in the literature in several homozygous or compound heterozygous individuals with ABCA4-related conditions (Stargardt disease 1, autosomal recessive retinitis pigmentosa, cone-rod dystrophy); this variant is typically associated with a milder phenotype and late-onset disease (Cella_2009_PMID:19217903; Burke_2012_PMID:22661473; Wiszniewski_2005_PMID:16103129; Kaway_2017_PMID:28611652; Zernant_2018_PMID:29848554). Furthermore, this variant is also seen to segregate with autosomal recessive retinitis pigmentosa, as seen in a large consanguineous family where this variant was identified in three affected compound heterozygotes (Ducroq_2006_PMID:16896346). The variant was identified in dbSNP (ID: rs1800553) and ClinVar (classified as pathogenic by Laboratory for Molecular Medicine, GeneDx and ten other laboratories, and as likely pathogenic by Mendelics and four other laboratories). The variant was identified in control databases in 1291 of 282848 chromosomes (10 homozygous) at a frequency of 0.004564 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 242 of 10368 chromosomes (freq: 0.02334), South Asian in 422 of 30614 chromosomes (freq: 0.01378), Other in 41 of 7222 chromosomes (freq: 0.005677), European (non-Finnish) in 488 of 129158 chromosomes (freq: 0.003778), Latino in 68 of 35440 chromosomes (freq: 0.001919), European (Finnish) in 15 of 25124 chromosomes (freq: 0.000597), African in 10 of 24970 chromosomes (freq: 0.000401), and East Asian in 5 of 19952 chromosomes (freq: 0.000251). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Gly1961 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. Further, functional analysis has demonstrated that this variant results in reduced basal and retinal-stimulated ATPase activities compared to control (Sun_2000_PMID:11017087). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

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.