rs1800553

chr1-94008251-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 9P and 5B. PM1 PM5 PP3 PP5_Strong BP4 BS2

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
• Clinical Significance: Pathogenic/Likely pathogenic/Pathogenic, low penetrance criteria provided, multiple submitters, no conflicts P:52 B:1 O:4
• Conservation: PhyloP100: 5.88

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]

ACMG classification

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
ABCA4	NM_000350.3	c.5882G>A	p.Gly1961Glu	missense_variant	42/50	ENST00000370225.4
ABCA4	XM_047416704.1	c.5660G>A	p.Gly1887Glu	missense_variant	41/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.5882G>A	p.Gly1961Glu	missense_variant	42/50	1	NM_000350.3	P1
ABCA4	ENST00000465352.1	n.298G>A		non_coding_transcript_exon_variant	3/6	5

Frequencies

GnomAD3 genomes AF: 0.00311 AC: 473 AN: 152092 Hom.: 3 Cov.: 32

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

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

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

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:52Benign:1Other:4

Revision: criteria provided, multiple submitters, no conflicts

LINK:

Submissions by phenotype

Severe early-childhood-onset retinal dystrophy Pathogenic:17Other:1

Likely pathogenic, criteria provided, single submitter	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	Based 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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
not provided, no classification provided	phenotyping only	GenomeConnect, 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jun 28, 2016	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. -
Likely pathogenic, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	-	identified in compound heterozygous state in affected individual/s with macular isease -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 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 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Arcensus	Feb 01, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Molecular Genetics, University of Zurich	Jan 30, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 17, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 01, 2021	PM1, PM3, PM5, PP2, PP3, PP5 -

not provided Pathogenic:9Other:2

Pathogenic, no assertion criteria provided	clinical testing	Department 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. -
not provided, no classification provided	literature only	Retina International	-	- -
not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 21, 2022	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 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2022	Published 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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 30, 2016	- -
Pathogenic, low penetrance, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This 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, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ABCA4: PM3:Very Strong, PP1:Strong, PM5, PM2:Supporting, PP3, PS3:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Cone-rod dystrophy 3 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jun 10, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Apr 14, 2021	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. -

Stargardt disease Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 25, 2021	- -
Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 28, 2020	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. -
Pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -

Age related macular degeneration 2 Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	Sep 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Sep 05, 2019	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: Pm1,PM5,PP3,PP5. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

Macular dystrophy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 22, 2021	This 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 provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Likely pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -

Retinal dystrophy Pathogenic:3

Pathogenic, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 17, 2019	- -
Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -

ABCA4-Related Disorders Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 08, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Variantyx, Inc.	Nov 04, 2022	This 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. -

ABCA4-related retinopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Intergen, Intergen Genetics and Rare Diseases Diagnosis Center

Aug 29, 2023

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Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2014

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Retinitis pigmentosa 19 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomics England Pilot Project, Genomics England

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ABCA4-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 18, 2024

The 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 submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

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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 submitter

clinical testing

Hadassah Hebrew University Medical Center

Jun 20, 2019

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Cone-rod dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Apr 23, 2019

ACMG categories: PS3,PM1,PM3,PP3,PP4 -

not specified Benign:1

Benign, flagged submission

clinical testing

Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital

Feb 11, 2020

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MACULAR DEGENERATION, AGE-RELATED, 2, SUSCEPTIBILITY TO Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jul 01, 2008

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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

Other links and lift over

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