rs61751374

Positions:

chr1-94043413-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM1PP5_Very_StrongBP4

The NM_000350.3(ABCA4):c.3113C>T(p.Ala1038Val) variant causes a missense change. The variant allele was found at a frequency of 0.00185 in 1,614,144 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 7 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:35O:1

Conservation

PhyloP100: 5.79

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]

ABCA4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a domain ABC transporter 1 (size 231) in uniprot entity ABCA4_HUMAN there are 317 pathogenic changes around while only 11 benign (97%) in NM_000350.3

PP5

Variant 1-94043413-G-A is Pathogenic according to our data. Variant chr1-94043413-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94043413-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-94043413-G-A is described in Lovd as [Pathogenic]. Variant chr1-94043413-G-A is described in Lovd as [Likely_benign]. Variant chr1-94043413-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-94043413-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.023493528). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3 linkuse as main transcript	c.3113C>T	p.Ala1038Val	missense_variant	21/50	ENST00000370225.4	NP_000341.2
ABCA4	XM_047416704.1 linkuse as main transcript	c.2891C>T	p.Ala964Val	missense_variant	20/49		XP_047272660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.3113C>T	p.Ala1038Val	missense_variant	21/50	1	NM_000350.3	ENSP00000359245	P1

Frequencies

GnomAD3 genomes

AF:

0.00164

AC:

249

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000917

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00622

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00220

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00168

AC:

422

AN:

251308

Hom.:

AF XY:

0.00157

AC XY:

213

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00545

Gnomad NFE exome

AF:

0.00223

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00187

AC:

2734

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00187

AC XY:

1359

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.00116

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00537

Gnomad4 NFE exome

AF:

0.00204

Gnomad4 OTH exome

AF:

0.00166

GnomAD4 genome

AF:

0.00164

AC:

249

AN:

152256

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

126

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000916

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00622

Gnomad4 NFE

AF:

0.00221

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00192

Hom.:

Bravo

AF:

0.00135

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00143

AC:

173

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.00154

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:35Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Severe early-childhood-onset retinal dystrophy

Pathogenic:11

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.3113C>T, NM_000350.3:c.2588G>C, NM_000350.3:c.5693G>A and NM_000350.3:c.1411G>A. Criteria applied: PM3_VSTR, PS3_MOD -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2003	- -
Likely pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The ABCA4 c.3113C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS3, PM3, PP5, BP4. Based on this evidence we have classified this variant as Likely Pathogenic. -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000350.2:c.3113C>T in the ABCA4 gene has an allele frequency of 0.006 in European(Finnish) subpopulation in the gnomAD database. The p.Ala1038Val (NM_000350.2:c.3113C>T) variant in the ABCA4 gene has been reported numerous times in association with autosomal recessive cone-rod dystrophy and Stargardt disease (PMID: 10958763; 11527935; 16103129; 25712131; 27939946). It was detected in multiple individuals with autosomal recessive Stargardt disease, compound heterozygous with c.5882G>A (p.Gly1961Glu), IVS40+5G>A (PMID:10958763), c.1988G>A (p.Trp663Ter) (PMID: 22312191). The patient's phenotype is highly specific for ABCA4 gene (PMID:10958763). Functional studies demonstrate that both the L541P/A1038V complex allele as well as the L541P and A1038V variants independently result in reduced ATPase activity; however, the affect of A1038V is milder compared to that of L541P alone or the L541P/A1038V complex allele (PMID: 11017087; 16103129; 25712131). Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP criteria applied: PS3; PM3_Strong; PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Hospital Muenster	Jan 08, 2019	ACMG categories: PS1,PS3,PP2,PP3,PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2016	- -
Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	Sep 01, 2016	- -
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_v1.3.4, 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 1 (MIM#248200). (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). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (492 heterozygotes, 2 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated ABC transporter domain (Pfam). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is very well reported (>20 times) in Stargardt disease patients. It usually occurs in cis with L541P as a more severe complex allele (German founder allele) but it has also been reported by itself with another pathogenic variant in trans with later onset disease. (ClinVar, PMID: 28118664, PMID 30718709) (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function causing mild disease. Using transfected HEK293 cells the authors demonstrated that this variant slightly reduced ATPase activity and that the mutant protein retained major structural features similar to that of wild-type (PMID: 25712131). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, no assertion criteria provided	research	Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	-	- -

not provided

Pathogenic:7Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 16, 2016	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1038 of the ABCA4 protein (p.Ala1038Val). This variant is present in population databases (rs61751374, gnomAD 0.6%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with Stargardt disease. It is commonly found in cis with p.Leu541Pro, which is thought to result in a more severe phenotype than the p.Ala1038Val variant alone (PMID: 9054934, 9973280, 10206579, 16103129, 19217903, 22312191, 24509150, 25712131). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7894). 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 not expected to disrupt ABCA4 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 11017087, 16103129, 25712131). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 14, 2023	- -
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, PM1, PM2:Supporting, PS3:Supporting, BP4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2024	Functional studies demonstrate that the p.(L541P)/p.(A1038V) complex allele as well as the p.(L541P) and p.(A1038V) variants independently result in reduced ATPase activity; however, the affect of p.(A1038V) is milder compared to that of p.(L541P) alone or the p.(L541P)/p.(A1038V) complex allele (PMID: 25712131, 11017087, 16103129); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 37510321, 37498587, 35120629, 35260635, 36460718, 32307445, 36672815, 29701254, 35076026, 37217489, 33749171, 34906470, 14517951, 12754711, 22312191, 28118664, 28147405, 29145636, 28327576, 28041643, 28224992, 29555955, 30093795, 38003421, 37734845, 31429209, 32531858, 25087612, 9054934, 16103129, 15494742, 9466990, 19074458, 19217903, 24509150, 23918662, 15579991, 26229699, 28044389, 26593885, 25910913, 28947085, 29847635, 29068140, 29925512, 30653986, 31456290, 34313030, 34327195, 34426522, 34008801, 33851411, 31589614, 33369172, 32037395, 30609409, 30204727, 30643219, 32581362, 32815999, 30718709, 30215852, 28559085, 32141364, 31980526, 32619608, 35836572, 35119454, Piccolo2022[abstract], 34946930, 34315337, 34647987, 10958763, 25712131, 11017087, 11527935, 11328725, 38064509) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -

Retinal dystrophy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Feb 25, 2021	- -
Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 07, 2019	- -

Stargardt disease

Pathogenic:3

Pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2024	The p.Ala1038Val variant in ABCA4 has been reported in >10 individuals with Stargardt disease in the compound heterozygous state. In many cases, it co-occurred with another pathogenic variant (p.Leu541Pro) as a complex allele, however it has also been found with other pathogenic variants in the absence of the Leu541Pro variant (Allikmets 1997 PMID: 9054934, Cremers 1998 PMID: 9466990, Maugeri 1999 PMID: 10090887, Rivera 2000 PMID: 10958763, Simonelli 2000 PMID: 10711710, Oh 2004 PMID: 15579991, Cella 2009 PMID: 19217903, Burke 2012 PMID: 22312191, Sciezynska 2016 PMID: 26593885, Jespersgaard 2019 PMID: 30718709). The complex allele with Leu541Pro has been associated with an earlier onset and more severe course of the disease, while the p.Ala1038Val variant alone has been linked to a milder presentation (Zhang 2015 PMID: 25712131). It also segregated with disease in at least 1 affected relative from 1 family (Burke 2012 PMID: 22312191). This variant has also been identified in the general population with the highest frequency found at 0.55% (353/64030) of Finnish chromosomes, including 7 total homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). In vitro functional studies provide some evidence that the p.Ala1038Val variant may impact protein function (Sun 2000 PMID: 11017087) and animal models in mice and frogs have shown that the complex variant with p.Leu541Pro causes Stargardt disease (Wiszniewski 2005 PMID: 16103129, Zhang 2015 PMID: 25712131). In summary, although additional studies are required to fully establish its clinical significance, this variant is a mild allele that meets criteria to be classified as likely pathogenic for autosomal recessive Stargardt disease and is not expected to cause disease in the homozygous state. It is expected to cause more severe disease when in compound heterozygosity with a more severe allele (such as a loss of function variant). ACMG/AMP Criteria applied: PM3_Strong, PP1, PS3_Supporting. -
Likely pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -

Age related macular degeneration 2

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Nov 23, 2018	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP2. -

ABCA4-related disorder

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 27, 2024	The ABCA4 c.3113C>T variant is predicted to result in the amino acid substitution p.Ala1038Val. This variant has been reported as causative for autosomal recessive Stargardt Disease (STGD) (see for example Lewis et al. 1999. PubMed ID: 9973280; Rozet et al. 1998. PubMed ID: 9781034). This variant is frequently detected on the same chromosome (in cis) with another ABCA4 variant, c.1622T>C (p.Leu541Pro), as the complex allele p.[Leu541Pro; Ala1038Val] in patients with autosomal recessive retinal dystrophy (Burke et al. 2012. PubMed ID: 22312191; Cella et al. 2009. PubMed ID: 19217903; Wiszniewski et al. 2005. PubMed ID: 16103129; Klevering et al. 2004. PubMed ID: 15494742). The complex allele is reported to cause a more severe phenotype than either variant individually (Zhang et al. 2015. PubMed ID: 25712131). This variant is reported in 0.56% of alleles in individuals of European (Finnish) descent in gnomAD. This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/7894/). Given all the evidence, we interpret c.3133C>T (p.Ala1038Val) both alone and as part of the complex allele p.[Leu541Pro;Ala1038Val] as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 27, 2017	Across a selection of the available literature, the c.3113C>T (p.Ala1038Val) missense variant has been identified in a compound heterozygous state in four individuals, including two siblings, with Stargardt disease (STGD) (Rivera et al. 2000; Burke et al. 2012). The p.Ala1038Val variant has also been reported as part of a complex allele with a second missense variant in 33 patients including four patients in a homozygous state, 28 patients in a compound heterozygous state, and one patient in a heterozygous state (Rivera et al. 2000; Briggs et al. 2001; Wiszniewski et al. 2005; Zhang et al. 2015; Zolnikova et al. 2017). The majority of these individuals were diagnosed with STGD. The p.Ala1038Val variant was reported in one of 510 controls in a heterozygous state (Allikmets et al. 1997; Rivera et al. 2000) and is reported at a frequency of 0.00551 in the European (Finnish) population of the Genome Aggregation Database. Two homozygotes were also reported, one each in the European (non-Finnish) and Latino populations. Expression in Xenopus laevis rods showed that the complex allele and second missense variant result in mislocalization of the protein, but the p.Ala1038Val variant protein had wild type localization. In the same study, expression in COS7 cells revealed that the rate of ATP hydrolysis of the complex allele is 68.1% of wild type (Wiszniewski et al. 2005). In another study, the basal activity of variant p.Ala1038Val protein was approximately 70% of wild type, but it was able to be stimulated by all-trans-retinal, suggesting that presence of this variant may still result in transport of the substrate (Zhang et al. 2015). However, in another study, while expression of variant p.Ala1038Val showed it produced protein levels comparable to wild type, it was defective in ATP binding and it had reduced basal ATPase activity and reduced all-trans-retinal-stimulated ATP hydrolysis (Sun et al. 2000). Based on the collective evidence, the p.Ala1038Val variant when present on a complex allele 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. -

Macular dystrophy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 22, 2021	_x000D_This variant was identified aspotentially compound heterozygous withNM_000350.3:c.1622T>C and NM_000350.3:c.5882G>A. Criteria applied: PM3_VSTR, PS3_MOD, PP3 -
Pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -

Cone-rod dystrophy 3

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	This variant was identified as compound heterozygous. -

not specified

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 04, 2019

The ABCA4 c.3113C>T;p.Ala1038Val variant (rs61751374) has been published in the literature in individuals with Stargardt disease and has been described as a common pathogenic allele (Allikments 1997, Burke 2012, Oh 2004, Rivera 2000). ARUP laboratories has also detected this variant with another likely pathogenic variant in an individual with a clinical diagnosis of Stargardt disease. The variant has also been described as segregating with disease in at least one family (Burke 2012). However, this variant has been published on the same chromosome with another variant, p.Leu541Pro (Cella 2009, Serapinas 2013) with one study implicating p.Leu541Pro as the pathogenic variant (Wiszniewski 2005). However, the p.Ala1038Val variant has been described in several affected individuals without the p.Leu541Pro variant (Rivera 2000), and it is listed as pathogenic in ClinVar (Variation ID: 7894). The alanine at codon 1038 is highly conserved, and while computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated, functional analyses indicate a defect in ATP hydrolysis (Sun 2000, Zhang 2015). Based on available information, this variant is considered to be likely pathogenic. References: Allikmets R et al. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet. 1997 15(3):236-46. Burke TR et al. Familial discordance in Stargardt disease. Mol Vis. 2012 18:227-33. Cella W et al. G1961E mutant allele in the Stargardt disease gene ABCA4 causes bull's eye maculopathy. Exp Eye Res. 2009 89(1):16-24. Oh KT et al. Electroretinographic findings in patients with Stargardt disease and fundus flavimaculatus. Retina. 2004 24(6):920-8. Rivera A et al. A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration. Am J Hum Genet. 2000 Oct;67(4):800-13. Serapinas D et al. Stargardt disease caused by a rare combination of double homozygous mutations. Medicina (Kaunas). 2013 49(8):386-91. 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 14(19):2769-78. Zhang N et al. Protein misfolding and the pathogenesis of ABCA4-associated retinal degenerations. Hum Mol Genet. 2015 Jun 1;24(11):3220-37. -

Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19;C3495438:Age related macular degeneration 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 18, 2021

- -

Retinitis pigmentosa

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

0.0029

BayesDel_noAF

Pathogenic

0.23

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Uncertain

0.44

Eigen

Benign

-0.068

Eigen_PC

Benign

0.19

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.71

M_CAP

Pathogenic

0.65

MetaRNN

Benign

0.023

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

1.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.24

REVEL

Uncertain

0.53

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0090

Vest4

0.74

MVP

0.91

MPC

0.20

ClinPred

0.019

GERP RS

5.9

Varity_R

0.39

gMVP

0.81

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over