ClinVar Miner

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

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Total submissions: 29
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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 2020-04-02 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
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 Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
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 not specified 2018-08-01 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
Invitae RCV000078670 SCV001229561 pathogenic not provided 2020-01-08 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 2020-01-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197193 SCV001367829 pathogenic Severe visual impairment; Macular dystrophy 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PP2,PP3,PP5. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198393 SCV001369317 likely pathogenic Progressive visual loss; Cone/cone-rod dystrophy; Blurred vision 2019-09-05 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM5. This variant was detected in heterozygous state.
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

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