rs76157638
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM5PP3PP5_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. G863E) has been classified as Likely pathogenic.
Frequency
Genomes: 𝑓 0.0042 ( 4 hom., cov: 33)
Exomes 𝑓: 0.0073 ( 42 hom. )
Consequence
ABCA4
NM_000350.3 missense, splice_region
NM_000350.3 missense, splice_region
Scores
8
8
3
Splicing: ADA: 0.9878
2
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
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_low_penetrance=1, Likely_pathogenic=2, not_provided=2, Uncertain_significance=2, Pathogenic=16}. 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 | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ABCA4 | NM_000350.3 | c.2588G>C | p.Gly863Ala | missense_variant, splice_region_variant | 17/50 | ENST00000370225.4 | NP_000341.2 | |
| ABCA4 | XM_047416704.1 | c.2366G>C | p.Gly789Ala | missense_variant, splice_region_variant | 16/49 | XP_047272660.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ABCA4 | ENST00000370225.4 | c.2588G>C | p.Gly863Ala | missense_variant, splice_region_variant | 17/50 | 1 | NM_000350.3 | ENSP00000359245 | P1 | |
| ABCA4 | ENST00000649773.1 | c.2366G>C | p.Gly789Ala | missense_variant, splice_region_variant | 16/19 | ENSP00000496882 |
Frequencies
GnomAD3 genomes 0.00424 AC: 645AN: 152198Hom.: 4 Cov.: 33
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GnomAD4 exome AF: 0.00735 AC: 10730AN: 1459996Hom.: 42 Cov.: 30 AF XY: 0.00714 AC XY: 5184AN XY: 726478
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GnomAD4 genome 0.00423 AC: 645AN: 152316Hom.: 4 Cov.: 33 AF XY: 0.00375 AC XY: 279AN XY: 74480
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ClinVar
Significance: Pathogenic/Likely pathogenic/Pathogenic, low penetrance
Submissions summary: Pathogenic:35Uncertain:2Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:11Other:1
| not provided, no classification provided | literature only | Retina International | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 18, 2016 | - - |
| 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) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 28, 2023 | - - |
| 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 | - - |
| 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 | - | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, low penetrance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | 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). - |
| 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. - |
| 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 - |
Severe early-childhood-onset retinal dystrophy Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Dec 20, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 27, 2022 | - - |
| 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, 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 | 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 | - - |
Retinitis pigmentosa Pathogenic:3
| 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. - |
| Pathogenic, no assertion criteria provided | research | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Apr 01, 2018 | - - |
| 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, criteria provided, single submitter | clinical testing | Blueprint Genetics | Aug 09, 2019 | - - |
| Pathogenic, no assertion criteria provided | research | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | Apr 01, 2018 | - - |
Stargardt disease Pathogenic:3
| 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. - |
| 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. - |
Cone-rod dystrophy 3 Pathogenic:2
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2008 | - - |
| 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 - |
Age related macular degeneration 2 Pathogenic:1Uncertain:1
| Uncertain significance, flagged submission | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Uncertain significance. - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, University Hospital Schleswig-Holstein | Oct 04, 2021 | - - |
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, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 04, 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 (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). 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 >40 homozygous individuals in the latest dataset (https://gnomad.broadinstitute.org/variant/1-94051698-C-G?dataset=gnomad_r4), which is evidence that this variant is likely to have reduced penetrance or low expressivity in the homozygous state. Several studies have supported that this variant is mild and only causes Stargardt disease 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.
REVEL
Pathogenic
Sift
Uncertain
D;.
Sift4G
Pathogenic
D;.
Polyphen
P;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at