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rs1800553

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 9P and 5B. PM1PM5PP3PP5_StrongBP4BS2

The NM_000350.3(ABCA4):c.5882G>A(p.Gly1961Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00341 in 1,614,012 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as other (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1961R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0031 ( 3 hom., cov: 32)
Exomes 𝑓: 0.0034 ( 41 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

7
6
2

Clinical Significance

Pathogenic/Likely pathogenic/Pathogenic, low penetrance criteria provided, multiple submitters, no conflicts P:51B:1O:4

Conservation

PhyloP100: 5.88
Variant links:
Genes affected
ABCA4 (HGNC:34): (ATP binding cassette subfamily A member 4) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. This protein is a retina-specific ABC transporter with N-retinylidene-PE as a substrate. It is expressed exclusively in retina photoreceptor cells, and the gene product mediates transport of an essental molecule, all-trans-retinal aldehyde (atRAL), across the photoreceptor cell membrane. Mutations in this gene are found in patients diagnosed with Stargardt disease, a form of juvenile-onset macular degeneration. Mutations in this gene are also associated with retinitis pigmentosa-19, cone-rod dystrophy type 3, early-onset severe retinal dystrophy, fundus flavimaculatus, and macular degeneration age-related 2. [provided by RefSeq, Sep 2019]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000350.3
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-94008252-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 236140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Cadd, PrimateAI, PROVEAN, REVEL [when FATHMM_MKL, MetaRNN, MutationAssessor, MutationTaster was below the threshold]
PP5
Variant 1-94008251-C-T is Pathogenic according to our data. Variant chr1-94008251-C-T is described in ClinVar as [other]. Clinvar id is 7888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=27, Benign=1, Pathogenic_low_penetrance=1, Likely_pathogenic=10, not_provided=3}. Variant chr1-94008251-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-94008251-C-T is described in Lovd as [Pathogenic]. Variant chr1-94008251-C-T is described in Lovd as [Likely_benign]. Variant chr1-94008251-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-94008251-C-T is described in Lovd as [Pathogenic]. Variant chr1-94008251-C-T is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.013598174).. Strength limited to SUPPORTING due to the PP5.
BS2
High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ABCA4NM_000350.3 linkuse as main transcriptc.5882G>A p.Gly1961Glu missense_variant 42/50 ENST00000370225.4
ABCA4XM_047416704.1 linkuse as main transcriptc.5660G>A p.Gly1887Glu missense_variant 41/49

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ABCA4ENST00000370225.4 linkuse as main transcriptc.5882G>A p.Gly1961Glu missense_variant 42/501 NM_000350.3 P1
ABCA4ENST00000465352.1 linkuse as main transcriptn.298G>A non_coding_transcript_exon_variant 3/65

Frequencies

GnomAD3 genomes
AF:
0.00311
AC:
473
AN:
152092
Hom.:
3
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000555
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00380
Gnomad ASJ
AF:
0.0239
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.0127
Gnomad FIN
AF:
0.000943
Gnomad MID
AF:
0.0222
Gnomad NFE
AF:
0.00325
Gnomad OTH
AF:
0.00478
GnomAD3 exomes
AF:
0.00470
AC:
1181
AN:
251452
Hom.:
9
AF XY:
0.00537
AC XY:
730
AN XY:
135906
show subpopulations
Gnomad AFR exome
AF:
0.000492
Gnomad AMR exome
AF:
0.00188
Gnomad ASJ exome
AF:
0.0237
Gnomad EAS exome
AF:
0.000272
Gnomad SAS exome
AF:
0.0138
Gnomad FIN exome
AF:
0.000508
Gnomad NFE exome
AF:
0.00348
Gnomad OTH exome
AF:
0.00570
GnomAD4 exome
AF:
0.00344
AC:
5025
AN:
1461802
Hom.:
41
Cov.:
31
AF XY:
0.00384
AC XY:
2792
AN XY:
727210
show subpopulations
Gnomad4 AFR exome
AF:
0.00108
Gnomad4 AMR exome
AF:
0.00177
Gnomad4 ASJ exome
AF:
0.0222
Gnomad4 EAS exome
AF:
0.000529
Gnomad4 SAS exome
AF:
0.0131
Gnomad4 FIN exome
AF:
0.00122
Gnomad4 NFE exome
AF:
0.00239
Gnomad4 OTH exome
AF:
0.00546
GnomAD4 genome
AF:
0.00311
AC:
473
AN:
152210
Hom.:
3
Cov.:
32
AF XY:
0.00321
AC XY:
239
AN XY:
74422
show subpopulations
Gnomad4 AFR
AF:
0.000554
Gnomad4 AMR
AF:
0.00379
Gnomad4 ASJ
AF:
0.0239
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.0127
Gnomad4 FIN
AF:
0.000943
Gnomad4 NFE
AF:
0.00325
Gnomad4 OTH
AF:
0.00473
Alfa
AF:
0.00457
Hom.:
6
Bravo
AF:
0.00284
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.00208
AC:
8
ESP6500AA
AF:
0.00113
AC:
5
ESP6500EA
AF:
0.00419
AC:
36
ExAC
AF:
0.00505
AC:
613
Asia WGS
AF:
0.00520
AC:
18
AN:
3478
EpiCase
AF:
0.00480
EpiControl
AF:
0.00451

ClinVar

Significance: Pathogenic/Likely pathogenic/Pathogenic, low penetrance
Submissions summary: Pathogenic:51Benign:1Other:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Severe early-childhood-onset retinal dystrophy Pathogenic:16Other:1
Likely pathogenic, criteria provided, single submitterclinical testingArcensusFeb 01, 2013- -
Likely pathogenic, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Likely pathogenic, criteria provided, single submitterclinical testing3billionJan 03, 2022Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007888, PMID:9295268, PS1_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000236140, PMID:22427542,NULL, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.76, 3CNET: 0.857, PP3_P). A missense variant is a common mechanism associated with Stargardt disease 1 (PP2_P). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submittercurationDepartment Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos UniversityDec 30, 2017- -
Likely pathogenic, criteria provided, single submitterresearchLupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine-identified in compound heterozygous state in affected individual/s with macular isease -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJul 21, 2022_x000D_This variant was identified in a patient with another variant NM_000350.3:c.67-2A>G Criteria applied: PM3_VSTR, PM5_STR, PP1_STR, PS3_MOD, PP3, PP4 -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJan 17, 2020This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabSep 10, 2021- -
Pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-This variant c.5882G>A (p.Gly1961Glu) in ABCA4 gene 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: Stone et al., 2017; Riera et al., 2017). 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 (Kobayashi et al., 2017). However, this variant appears to be significantly enriched in individuals with Stargardt compared to the general population (Lee et al., 2017). This variant appears to be associated with milder and/or later onset disease (Lee et al., 2017). This variant has been reported to affect ABCA4 protein function (Sun et al. 2000). The amino acid Gly at position 1961 is changed to a Glu changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT and the residue is conserved across species. The amino acid change p.Gly1961Glu in ABCA4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification providedphenotyping onlyGenomeConnect, ClinGen-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. -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, Univ. Regensburg, Univ. RegensburgJan 01, 2016- -
Pathogenic, criteria provided, single submitterclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversityJun 28, 2016The 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. -
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterJul 26, 2022- -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteSep 02, 2022Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Stargardt disease (MIM#248200) and other eye conditions (OMIM). (I) 0106 - This gene is associated with autosomal recessive disease (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 31522899). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to glutamic acid. (I) 0252 - This variant is homozygous. (I) 0305 - Variant is present in gnomAD >=0.01 and <0.03 for a recessive condition (v2: 1271 heterozygotes, 10 homozygotes). (I) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (26 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0600 - Variant is located in the annotated NBD2 domain (PMID: 29847635). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. p.(Gly1961Ala) has been previously reported in patients with Stargardt disease (ClinVar, PMID: 22427542). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals with mild and later onset Stargardt disease (ClinVar, PMID: 22661473, PMID: 28327576, PMID: 28130426, PMID: 29925512). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function, where transfected cells displayed reduced ATPase activity and substrate binding (PMID: 29847635). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 01, 2008- -
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Molecular Genetics, University of ZurichJan 30, 2021- -
Pathogenic, criteria provided, single submitterclinical testingLaboratory of Medical Genetics, National & Kapodistrian University of AthensOct 01, 2021PM1, PM3, PM5, PP2, PP3, PP5 -
not provided Pathogenic:9Other:2
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 21, 2022The 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 -
not provided, no classification providedliterature onlyRetina International-- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
not provided, no classification providedliterature onlyNEI Ophthalmic Genomics Laboratory, National Institutes of Health-- -
Pathogenic, low penetrance, criteria provided, single submitterclinical testingInvitaeJan 31, 2024This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1961 of the ABCA4 protein (p.Gly1961Glu). This variant is present in population databases (rs1800553, gnomAD 2.3%), including at least one homozygous and/or hemizygous individual. 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 in heterozygous carriers (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). 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, 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). -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-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. -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Nov 30, 2016- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2024ABCA4: PM3:Very Strong, PP1:Strong, PM5, PM2:Supporting, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitterclinical testingGeneDxApr 12, 2022Published functional studies demonstrate this variant results in reduced ATPase activity (Sun et al., 2000); Reported as pathogenic in ClinVar by different clinical laboratories but additional evidence is not available (ClinVar Variation ID: 7888; ClinVar); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25921964, 25082885, 26593885, 28611652, 9295268, 22661473, 31980526, 32581362, 31589614, 32000842, 32619608, 33090715, 32783370, 32815999, 33301772, 32037395, 10958763, 15614537, 21786275, 16103129, 22025579, 22264887, 24265693, 25097241, 25087612, 11017087, 19217903, 25640233, 27775217, 27884173, 27535533, 26247787, 27414126, 28327576, 28044389, 29555955, 28130426, 29847635, 28224992, 30060493, 28181551, 29114839, 28492530, 28118664, 29769798, 28157192, 30609409, 30924848, 29925512, 30718709, 29765157, 28559085, 30156925, 18161617, 31814694, 32141364, 31456290, 32036094, 32845068, 34327195, 34426522, 33909047, 34008892, 33302505, 31573552) -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Cone-rod dystrophy 3 Pathogenic:4
Pathogenic, no assertion criteria providedresearchDivision of Human Genetics, Children's Hospital of PhiladelphiaJun 10, 2016- -
Pathogenic, criteria provided, single submitterclinical testingJohns Hopkins Genomics, Johns Hopkins UniversityApr 14, 2021This 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. -
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 01, 2008- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJan 01, 2019- -
Stargardt disease Pathogenic:4
Pathogenic, no assertion criteria providedresearchSharon lab, Hadassah-Hebrew University Medical CenterJun 23, 2019- -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMay 28, 2020The 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. -
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 25, 2021- -
Pathogenic, no assertion criteria providedresearchDepartment of Clinical Genetics, Copenhagen University Hospital, RigshospitaletApr 01, 2018- -
Age related macular degeneration 2 Pathogenic:3
Likely pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaSep 05, 2019This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: Pm1,PM5,PP3,PP5. -
Pathogenic, criteria provided, single submitterclinical testingGenomics England Pilot Project, Genomics England-- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+Sep 01, 2016- -
Macular dystrophy Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterNov 22, 2021This variant was identified aspotentially compound heterozygous with NM_000350.3:c.3113C>T and NM_000350.3:c.1622T>C. Criteria applied: PM3_VSTR, PS3_SUP, PM5_STR, PP3 -
Likely pathogenic, no assertion criteria providedresearchDepartment of Clinical Genetics, Copenhagen University Hospital, RigshospitaletApr 01, 2018- -
Likely pathogenic, no assertion criteria providedresearchNIHR Bioresource Rare Diseases, University of CambridgeJan 01, 2015- -
Retinal dystrophy Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsAug 17, 2019- -
Pathogenic, criteria provided, single submitterresearchDept Of Ophthalmology, Nagoya UniversityOct 01, 2023- -
Likely pathogenic, no assertion criteria providedresearchNIHR Bioresource Rare Diseases, University of CambridgeJan 01, 2015- -
ABCA4-Related Disorders Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMay 08, 2017The 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. -
Pathogenic, criteria provided, single submitterclinical testingVariantyx, Inc.Nov 04, 2022This is a nonsynonymous variant in the ABCA4 gene (OMIM 601691). Biallelic pathogenic variants in this gene have been associated with autosomal recessive ABCA4-related disorders. This variant has been reported in the homozygous or compound heterozygous state in many individuals with mild or late-onset ABCA4-related disease (PMID: 30060493, 29555955, 28559085, 19074458, 28181551) (PM3_Strong). Additionally, this variant has been shown to confer a moderate risk (~3-fold) for age-related macular degeneration (PMID: 25921964). Functional studies have shown that this variant alters ABCA4 protein function (PMID: 11017087, 29847635) (PS3). An alternate amino acid change at this position (p.Gly1961Arg) has been previously reported as pathogenic in affected individuals (PMID: 23755871, 19074458, 26780318, 28118664) (PM5). Multiple computational algorithms predict a deleterious effect for this amino acid substitution (PP3). This variant has a 1.378% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/). Based on current evidence, this variant is classified as pathogenic for autosomal recessive ABCA4-related disorders. -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsSep 07, 2014- -
ABCA4-related retinopathy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingIntergen, Intergen Genetics and Rare Diseases Diagnosis CenterAug 29, 2023- -
Retinitis pigmentosa 19 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGenomics England Pilot Project, Genomics England-- -
ABCA4-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJan 18, 2024The ABCA4 c.5882G>A variant is predicted to result in the amino acid substitution p.Gly1961Glu. This variant has been reported many times in the compound heterozygous state in individuals with retinal dystrophy and has been associated with later-onset and milder retinal phenotypes (see for examples Cella et al. 2009. PubMed ID: 19217903, Lewis et al. 1999. PubMed ID: 9973280, Allikmets et al. 1997. PubMed ID: 9295268, Fujinami et al. 2013. PubMed ID: 23769331). This variant is documented with a global allele frequency of 0.46% in gnomAD, including several homozygotes (http://gnomad.broadinstitute.org/variant/1-94473807-C-T). This allele frequency is relatively high and consistent with this variant causing a more mild and later-onset retinal phenotype (Burke et al. 2012. PubMed ID: 22661473). However, when this variant is present in cis with other pathogenic ABCA4 variants as a complex allele, it has been reported to cause severe retinal phenotypes (Burke et al. 2012. PubMed ID: 22661473). Given the evidence, we interpret c.5882G>A (p.Gly1961Glu), both alone and as part of a complex allele, as pathogenic. -
Retinitis pigmentosa Pathogenic:1
Likely pathogenic, criteria provided, single submittercurationBroad Center for Mendelian Genomics, Broad Institute of MIT and Harvard-The p.Gly1961Glu variant in ABCA4 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS3, PM5, PP3, PP5. Based on this evidence we have classified this variant as likely pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -
Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingHadassah Hebrew University Medical CenterJun 20, 2019- -
Cone-rod dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University Hospital MuensterApr 23, 2019ACMG categories: PS3,PM1,PM3,PP3,PP4 -
not specified Benign:1
Benign, flagged submissionclinical testingAl Jalila Children's Genomics Center, Al Jalila Childrens Speciality HospitalFeb 11, 2020- -
MACULAR DEGENERATION, AGE-RELATED, 2, SUSCEPTIBILITY TO Other:1
risk factor, no assertion criteria providedliterature onlyOMIMJul 01, 2008- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.85
BayesDel_addAF
Uncertain
0.10
D
BayesDel_noAF
Pathogenic
0.39
Cadd
Pathogenic
27
Dann
Uncertain
1.0
DEOGEN2
Uncertain
0.74
D;D
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.45
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D
MetaRNN
Benign
0.014
T;T
MetaSVM
Uncertain
0.72
D
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.81
D
REVEL
Pathogenic
0.76
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
.;D
Vest4
0.96
MVP
0.95
MPC
0.53
ClinPred
0.071
T
GERP RS
5.3
Varity_R
0.93
gMVP
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1800553; hg19: chr1-94473807; COSMIC: COSV64673416; COSMIC: COSV64673416; API