rs76157638

chr1-94051698-C-Gchr1-94051698-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM5 PP3 PP5_Strong

The NM_000350.3(ABCA4):c.2588G>C(p.Gly863Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00706 in 1,612,312 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as other (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G863R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0042 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0073 (42 hom.)
• Consequence: ABCA4 NM_000350.3 missense, splice_region
• Scores: Splicing: ADA: 0.9878
• Clinical Significance: Pathogenic/Likely pathogenic/Pathogenic, low penetrance criteria provided, multiple submitters, no conflicts P:36 U:2 O:2
• Conservation: PhyloP100: 7.04

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 Likely_pathogenic. Variant got 9 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, 4 uncertain in NM_000350.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-94051698-C-T is described in Lovd as [Likely_pathogenic].
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-94051698-C-G is Pathogenic according to our data. Variant chr1-94051698-C-G is described in ClinVar as [other]. Clinvar id is 7879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=18, Pathogenic_low_penetrance=1, Likely_pathogenic=2, Uncertain_significance=2, not_provided=2}. Variant chr1-94051698-C-G is described in Lovd as [Pathogenic]. Variant chr1-94051698-C-G is described in Lovd as [Likely_pathogenic]. Variant chr1-94051698-C-G is described in Lovd as [Likely_benign]. Variant chr1-94051698-C-G is described in Lovd as [Likely_pathogenic]. Variant chr1-94051698-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3	c.2588G>C	p.Gly863Ala	missense_variant, splice_region_variant	17/50	ENST00000370225.4
ABCA4	XM_047416704.1	c.2366G>C	p.Gly789Ala	missense_variant, splice_region_variant	16/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.2588G>C	p.Gly863Ala	missense_variant, splice_region_variant	17/50	1	NM_000350.3	P1
ABCA4	ENST00000649773.1	c.2366G>C	p.Gly789Ala	missense_variant, splice_region_variant	16/19

Frequencies

GnomAD3 genomes AF: 0.00424 AC: 645 AN: 152198 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00780

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00436 AC: 1096 AN: 251244 Hom.: 6 AF XY: 0.00467 AC XY: 634 AN XY: 135782

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00200

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00804

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00735 AC: 10730 AN: 1459996 Hom.: 42 Cov.: 30 AF XY: 0.00714 AC XY: 5184 AN XY: 726478

Gnomad4 AFR exome AF: 0.00117

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.00214

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00193

Gnomad4 FIN exome AF: 0.00182

Gnomad4 NFE exome AF: 0.00896

Gnomad4 OTH exome AF: 0.00623

GnomAD4 genome AF: 0.00423 AC: 645 AN: 152316 Hom.: 4 Cov.: 33 AF XY: 0.00375 AC XY: 279 AN XY: 74480

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00781

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00686 Hom.: 3

Bravo AF: 0.00394

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00674 AC: 58

ExAC AF: 0.00497 AC: 603

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00665

EpiControl AF: 0.00782

ClinVar

Significance: Pathogenic/Likely pathogenic/Pathogenic, low penetrance

Submissions summary: Pathogenic:36 Uncertain:2 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:11 Other:1

Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 28, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	The ABCA4 c.2588G>C; p.Gly863Ala variant (rs76157638) is reported in the medical literature in individuals with ABCA4-related diseases in the homozygous or compound heterozygous state (Bertelsen 2014, Birtel 2018, Duncker 2015, Khan 2018, Zernant 2017). The variant is reported as pathogenic or likely pathogenic by several sources in the ClinVar database (Variation ID: 7879) but is also listed in the European (non-Finnish) population with an allele frequency of 0.8% (1012/1209076 alleles, including 7 homozygotes) in the Genome Aggregation Database. This variant has been described as a European founder variant and is implicated as a mild pathogenic variant (Maugeri 1999, Zernant 2017). The glycine at this position is highly conserved but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. However, the variant has also been shown to cause an alternative splice removing one amino acid (Maugeri 1999). Considering available information, this variant is classified as likely pathogenic but may result in a milder clinical phenotype. References: Bertelsen M et al. Generalized choriocapillaris dystrophy, a distinct phenotype in the spectrum of ABCA4-associated retinopathies. Invest Ophthalmol Vis Sci. 2014 Apr 29;55(4):2766-76. Birtel J et al. Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy. Sci Rep. 2018 Mar 19;8(1):4824. Duncker T et al. Quantitative fundus autofluorescence distinguishes ABCA4-associated and non-ABCA4-associated bull's-eye maculopathy. Ophthalmology. 2015 Feb;122(2):345-55. Khan KN et al. Early Patterns of Macular Degeneration in ABCA4-Associated Retinopathy. Ophthalmology. 2018 May;125(5):735-746. Maugeri A et al. The 2588G-->C mutation in the ABCR gene is a mild frequent founder mutation in the Western European population and allows the classification of ABCR mutations in patients with Stargardt disease. Am J Hum Genet. 1999 Apr;64(4):1024-35. Zernant J et al. Frequent hypomorphic alleles account for a significant fraction of ABCA4 disease and distinguish it from age-related macular degeneration. J Med Genet. 2017 Jun;54(6):404-412. -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 18, 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 alanine, which is neutral and non-polar, at codon 863 of the ABCA4 protein (p.Gly863Ala). This variant is present in population databases (rs76157638, gnomAD 0.8%), including at least one homozygous and/or hemizygous individual. This variant has been reported in the compound-heterozygous state in several individuals and families affected with Stargardt disease and retinitis pigmentosa (PMID: 10612508, 10634594, 10090887, 12192456, 9054934, 23695285, 26247787, 25097241, 28041643). However, studies suggest that this is a mild variant that may only cause disease when in combination with a severe, pathogenic ABCA4 variant (PMID: 10090887). ClinVar contains an entry for this variant (Variation ID: 7879). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this variant results in the production of two transcripts: one that lacks glycine 863 and the other with the Gly863Ala missense change (PMID: 10090887). Additional functional studies have shown that this missense change affects nucleotide hydrolysis and reduces the interaction of ABCA4 with 11-cis-retinal (PMID: 11919200, 23144455, 11017087). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, this variant is reported to cause autosomal recessive Stargardt disease and retinitis pigmentosa. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the ABCA4 gene, and as it may not result in disease in the homozygous state, it has been classified as Pathogenic (low penetrance). -
not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ABCA4: PM3:Very Strong, PM2:Supporting, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2022	Most common allele among individuals with Stargardt disease in Northern Europe, representing roughly 20-30% of disease associated alleles (Maugeri et al., 1999).; RNA studies demonstrated that the c.2588 G>C nucleotide change results in the utilization of an alternate splice site, which could produce an abnormal protein lacking the Gly863 residue (aka p.G863del) (Maugeri et al., 1999); Published functional studies demonstrate that G863A has minimal effect on ATP hydrolysis, but significantly reduces interaction of the nucleotide binding domain 1 of the ABCA4 protein with 11-cis-retinal (Biswas-Fiss et al., 2012); One study proposes G863A exhibits pathogenicity only when observed in cis with the common N1868I variant (Zernant et al., 2017); This variant is associated with the following publications: (PMID: 25082885, 25884411, 25346251, 25444351, 25712131, 25922843, 25097241, 9054934, 28446513, 28248825, 27939946, 28044389, 30643219, 30609409, 30718709, 30215852, 28559085, 32845050, 31456290, 25283059, 24082139, 24154662, 25333069, 11017087, 20981092, 22264887, 12192456, 11919200, 25363634, 23144455, 10612508, 23695285, 24713488, 25681002, 28327576, 26247787, 10090887, 28041643, 28341476, 29555955, 3002862, 29310964, 29431110, 29162642, 30563929, 29925512, 32467599, 31980526, 32036094, 32581362, 34426522, 34570182, 32619608, 32913387, 32815999, 32037395, 11527935) -

Severe early-childhood-onset retinal dystrophy Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Dec 20, 2021	- -
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	Genetics and Molecular Pathology, SA Pathology	Jul 20, 2020	Although common this variant has been reported in the compound-heterozygous state in several individuals and families affected with Stargardt disease and retinitis pigmentosa (PMID: 10612508, 10634594, 10090887, 12192456, 9054934, 23695285, 26247787, 25097241, 28041643). However, studies suggest that this is a mild variant that may only cause disease when in combination with a severe, pathogenic ABCA4 variant (PMID: 10090887). ClinVar contains an entry for this variant (Variation ID: 7879). Experimental studies have shown that this variant results in the production of two transcripts: one that lacks glycine 863 and the other with the Gly863Ala missense change (PMID: 10090887). Additional functional studies have shown that this missense change affects nucleotide hydrolysis and reduces the interaction of ABCA4 with 11-cis-retinal (PMID: 11919200, 23144455, 11017087). In summary, this variant is reported to cause autosomal recessive Stargardt disease and retinitis pigmentosa. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the ABCA4 gene, and as it may not result in disease in the homozygous state, it has been classified as Pathogenic (low penetrance). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 31, 2023	This variant was identified together with NM_000350.3:c.1622T>C, NM_000350.3:c.3113C>T, NM_000350.3:c.5693G>A and NM_000350.3:c.1411G>A Criteria applied: PM3_VSTR, PS3_MOD, PM5, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.3, 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 retinal dystrophy, Stargardt disease 1 (MIM#248200) and cone-rod dystrophy (MIM#604116). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Affected siblings can have variable age of onset and severity of disease (PMID:31522899). 0200 - Variant is predicted to result in a missense amino acid change from glycine to alanine. This variant also leads to aberrant splicing resulting in the in-frame deletion of this residue (p.(Gly863del)) in approximately 50% of transcripts (PMID:10090887). (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2, European subpopulation) <0.01 for a recessive condition (1200 heterozygotes, 7 homozygotes). (SP) 0309 - An alternative amino acid change p.(Gly863Glu) at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Nucleotide Binding Domain 1 (NBD1) (PMID: 11444963). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The frequently reported p.[Gly863Ala, Gly863del] variant has strong evidence supporting pathogenicity when in cis with p.(Asn1868Ile) and in trans with a second pathogenic variant. This variant is unlikely to be disease-causing on its own, however the complex allele is fully penetrant and is associated with mild to moderate disease with variable phenotype, depending on the variant on the opposite allele (ClinVar, PMID:9054934, 28044389, 28446513, 32278709). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant segregates with disease, in a compound heterozygous state with a second pathogenic allele, in at least 5 families in the literature (PMID: 10612508, 31522899). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant leads to reduced protein expression, ATP-binding affinity, and ATP hydrolysis in in vitro studies (PMID: 11017087, 11919200). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 27, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2008	- -

Retinitis pigmentosa Pathogenic:3

Pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Apr 01, 2021	The p.Gly863Ala 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, PM2, PM3, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -
Likely pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -

Retinal dystrophy Pathogenic:3

Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 09, 2019	- -

Stargardt disease Pathogenic:3

Pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 10, 2018	The p.Gly863Ala variant in ABCA4 has been reported in >25 individuals with Starg ardt disease in compound heterozygous state with a second ABCA4 variant (Allikme ts 1997, Maugeri 1999, Zhang 1999, Heathfield 2013), and segregated with disease in 3 affected relatives in one family (Zhang 1999). Available evidence suggests that p.Gly863Ala is a mild variant and causes disease when there is a severe va riant on the other allele. This variant has also been identified in 0.79% (998/1 26588) of European chromosomes by the Genome Aggregation Consortium (gnomAD, htt p://gnomad.broadinstitute.org; dbSNP rs76157638). This frequency is consistent w ith the p.Gly863Ala variant being one of the most common ABCA4 variants in patie nts with Stargardt disease in the European population. This variant was demonstr ated to cause aberrant splicing and lead to deletion of the glycine residue at p osition 863 (p.Gly863del) in half of the transcripts from this allele and the mi ssense p.Gly863Ala change in the other half in patient cells (Maugeri 1999). Bot h of these variants had impaired protein activity in in vitro studies (Maugeri 1 999, Sun 2000, Suarez 2002). In summary, this variant meets our criteria to be c lassified as pathogenic for Stargardt disease in an autosomal recessive manner b ased upon its co-occurrence in trans with other pathogenic variants in patients and functional evidence. ACMG/AMP Criteria applied: PM3_Very Strong, PS3_Moderat e, PP1. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 24, 2022	Variant summary: ABCA4 c.2588G>C (p.Gly863Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a canonical 3' acceptor site and three predict the variant creates a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (e.g. Maugeri_1999). The variant produces a mixture of two different transcripts, one where the use of a cryptic 3' acceptor site causes a 3bp deletion (resulting in deletion of Gly863), and the other unaffected by splicing (resulting in Gly863Ala). The variant allele was found at a frequency of 0.0044 in 251244 control chromosomes, predominantly at a frequency of 0.008 within the Non-Finnish European subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 6-fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCA4 causing Stargardt Disease phenotype (0.0014), suggesting that the variant may be a benign polymorphism found primarily in populations of Non-Finnish European origin. However, c.2588G>C has been reported in the literature in the compound heterozygous state in many individuals affected with Stargardt Disease, including in at least one family where it segregated with the disease phenotype (e.g. Maugeri_1999, Zhang_1999, Heathfield_2013, Weisschuh_2020). It has been proposed that c.2588G>C is a mild founder variant in the western European population, which causes Stargardt Disease only in combination with a severe pathogenic variant on the second allele (e.g. Maugeri_1999). Several publications report experimental evidence evaluating an impact on protein function and have found that both Gly863del and Gly863Ala reduce ATPase activity and that Glu863Ala severely impairs interaction with 11-cis-retinal (e.g. Sun_2000, Suarez_2002, Biswas-Fiss_2012). Many submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and the overwhelming majority classified the variant as either pathogenic (n= 14) or likely pathogenic (n=6). Based on the evidence outlined above, the variant was classified as pathogenic. -

Cone-rod dystrophy 3 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Oct 23, 2015	he c.2588G>C (p.Gly863Ala) missense variant has been reported in several individuals with Stargardt disease (Maugeri A et al., 1999) as well as advanced cone and rod dysfunction (Gerth et al. 2002). It has been seen in trans with other known pathogenic variants in the ABCA4 gene of affected individuals (Heathfield L et al. 2013). In addition, in vitro studies showed that the function of this variant is highly attenuated (Biswas-Fiss et al. 2012). The frequency of this variant in the population databases is lower than the disease allele frequency for the disease and the ancestral amino acid is conserved throughout evolution. Together, the c.2588G>C (p.Gly863Ala) missense variant meets our criteria for Likely Pathogenic -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2008	- -

Age related macular degeneration 2 Pathogenic:1 Uncertain:1

Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Oct 04, 2021	- -
Uncertain significance, flagged submission	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Uncertain significance. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 11, 2014

The c.2588G>C (p.G863A) alteration is located in exon 17 (coding exon 17) of the ABCA4 gene. This alteration results from a G to C substitution at nucleotide position 2588, causing the glycine (G) at amino acid position 863 to be replaced by an alanine (A). The heterozygous missense change is somewhat rare in population databases:_x000D_ Based on data from the NHLBI Exome Sequencing Project (ESP), the ABCA4 c.2588G>C alteration was observed in 68 among 13006 total alleles studied (0.52%). The alteration was observed in the 1000 Genomes Project in 1 among 2098 total alleles studied (0.05%). Based on data from the Genome Aggregation Database (gnomAD), the c.2588G>C alteration was observed among 0.43% (1202/276994) of total alleles studied, having been observed in 0.79% (998/126588) European (non-Finnish) alleles. Rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012; please note that some variants may appear to be rare due to ethnic underrepresentation in the database)._x000D_ _x000D_ IF USED, PULL THESE INTO REFERENCES:_x000D_ Kryukov GV, et al. (2007) Am J Hum Genet 80:727-739. Tennessen JA, et al. (2012) Science 337(64):64-69. The alteration has been observed in affected individuals: _x000D_ The c.2588G>C alteration has been observed in multiple individuals with retinal dystrophy (Maugeri. 2002). It one of the highest frequency autosomal recessive disease mutation in European populations (Maugeri. 2002). The alteration is conserved throughout evolution:_x000D_ The p.G863 amino acid is completetly conserved in available vertebrate species. Functional analysis reveals a damaging effect of the amino acid alteration: _x000D_ Functional analysis demonstrated that the p.G863A alteration significantly decreased the rates of nucleotide hydrolysis as well as the binding affinities of the protein (Suárez, 2002) In silico prediction is conflicting:_x000D_ The p.G863A alteration is predicted to be benign by Polyphen and deleterious by SIFT in silico analyses. Based on the available evidence, this alteration is classified as pathogenic. -

Retinitis pigmentosa 19 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Mar 07, 2023

This variant was identified together with NM_000350.3:c.2828G>A._x000D_ Criteria applied: PM3_VSTR, PS3_MOD, PM5, PP1, PP3 -

ABCA4-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 18, 2024

The ABCA4 c.2588G>C variant is predicted to result in the amino acid substitution p.Gly863Ala. This variant is also predicted to alter splicing based on available splicing prediction programs (Alamut Visual Plus v1.6.1). This variant is the first nucleotide of exon 17 and a functional study using RT-PCR analysis confirmed that this variant results in a mixture of predicted proteins either lacking one amino acid (p.Gly863del) or carrying the p.Gly863Ala substitution (Maugeri et al. 1999. PubMed ID: 10090887). This variant is reported in 0.78% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including 7 homozygous individuals, which is evidence that this variant does not cause disease in the homozygous state. Several studies have supported that this variant is mild and only causes Stargardt disease (STGD) when in trans (on the opposite chromosome) with a severe ABCA4 pathogenic variant (Maugeri et al. 1999. PubMed ID: 10090887; Allikmets et al. 1997. PubMed ID: 9054934; Papaioannou et al. 2000. PubMed ID: 10634594; Suárez et al. 2002. PubMed ID: 11919200). This variant has also been found in cis (on the same chromosome) with another pathogenic variant (c.6088C>T, p.Arg2030*) in two siblings, who carried another pathogenic variant in trans (Song et al. 2015. PubMed ID: 26247787). Functional studies demonstrated that this variant results in a decrease of both basal and retinal-stimulated ATPase activity (Sun et al. 2000. PubMed ID: 11017087). This variant is interpreted as pathogenic. -

Stargardt disease 3 Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana

-

- -

Cone-rod dystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Peripheral neuropathy;C4520679:Abnormal macular morphology Uncertain:1

Uncertain significance, flagged submission

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 28, 2013

- -

Age-related macular degeneration;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Pathogenic and reported on 02-21-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.025	T;T
MetaSVM	Uncertain	0.063	D
MutationAssessor	Pathogenic	3.2	M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.7	D;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0020	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		0.86	P;.
Vest4		0.84
MVP		0.93
MPC		0.46
ClinPred		0.063	T
GERP RS		4.9
Varity_R		0.83
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.84		Position offset: -3

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

Publications

LitVar

Other links and lift over

dbSNP: rs76157638; hg19: chr1-94517254; COSMIC: COSV64675027;