ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.3113C>T (p.Ala1038Val) (rs61751374)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 26
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000085549 SCV000227765 pathogenic not provided 2016-11-16 criteria provided, single submitter clinical testing
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000008348 SCV000281861 pathogenic Stargardt disease 1 2016-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000085549 SCV000511890 pathogenic not provided 2018-08-03 criteria provided, single submitter clinical testing The A1038V pathogenic variant in the ABCA4 gene has been reported numerous times in association with autosomal recessive cone-rod dystrophy and Stargardt disease (Rivera et al., 2000; Briggs et al. et al., 2001; Webster et al., 2001; Braun et al., 2013). In the literature, this variant often occurs together on the same allele, in cis, with L541P, which together is considered to represent a German founder allele (Rivera et al., 2000; Briggs et al., 2001; Webster et al., 2001; Wiszniewski et al., 2005). However, both the L541P and A1038V have been observed independently in trans with another pathogenic variant in individuals with Stargardt disease (Rivera et al., 2000; Briggs et al., 2001; Burke et al., 2012). 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 (Sun et al., 2000; Wiszniewski et al., 2005; Zhang et al., 2015). We interpret A1038V as a pathogenic variant when present independently or when occurring together in cis with L541P.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000085549 SCV000692634 pathogenic not provided 2020-02-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000787493 SCV000711770 likely pathogenic Stargardt disease 2018-01-31 criteria provided, single submitter clinical testing The p.Ala1038Val variant in ABCA4 has been reported in several individuals with Stargardt disease in the compound heterozygous state. In the majority of cases, it co-occured with another pathogenic variant (p.Leu541Pro) as a complex allele (Allikmets 1997, Cremers 1998, Maugeri 1999, Rivera 2000, Simonelli 2000, Oh 200 4, Cella 2009 Burke 2012, Sciezynska 2016), which has been associated with an ea rlier onset and more severe course of the disease, while the p.Ala1038Val varian t alone has been linked to a milder presentation (Zhang 2015). This variant has also been identified in the general population with the highest frequency found at 0.4% (28/6606) of Finnish chromosomes by the Exome Aggregation Consortium (Ex AC, http://exac.broadinstitute.org; dbSNP rs61751374). Although this variant is seen in the general population, its frequency is consistent with a recessive car rier frequency. In vitro functional studies provide some evidence that the p.Ala 1038Val variant may impact protein function (Sun 2000, ) and animal models in mi ce and frogs have shown that the complex variant causes Stargardt disease (Wiszn iewski 2005, Zhang 2015). In summary, although additional studies are required t o fully establish its clinical significance, the p.Ala1038Val variant is likely pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000014 SCV000883315 likely pathogenic not specified 2019-03-04 criteria provided, single submitter clinical testing 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.
Fulgent Genetics,Fulgent Genetics RCV000763046 SCV000893527 pathogenic Cone-rod dystrophy 3; Age-related macular degeneration 2; Stargardt disease 1; Retinitis pigmentosa 19 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778259 SCV000914431 pathogenic ABCA4-Related Disorders 2017-06-27 criteria provided, single submitter clinical testing 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.
Blueprint Genetics RCV000505109 SCV001239978 pathogenic Retinal dystrophy 2019-08-07 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196125 SCV001366612 pathogenic Hypermetropia; Reduced visual acuity; Granular macular appearance 2019-03-23 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP2,PP3. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197076 SCV001367711 pathogenic Visual impairment 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197158 SCV001367794 pathogenic Pigmentary retinopathy; Central scotoma; Macular degeneration; Blurred vision 2018-11-23 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP2,PP3. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197468 SCV001368221 pathogenic Visual loss; Retinal dystrophy 2019-08-21 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PP2,PP3,PP5. This variant was detected in homozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001199291 SCV001370368 pathogenic Macular degeneration; Visual field defect; Macular atrophy; Photoreceptor layer loss on macular OCT 2019-04-06 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP2,PP3. This variant was detected in heterozygous state.
Invitae RCV000085549 SCV001417577 pathogenic not provided 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1038 of the ABCA4 protein (p.Ala1038Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs61751374, ExAC 0.4%). This variant has been reported in several individuals and families affected with Stargardt disease (PMID: 9054934, 9973280, 22312191). It is also commonly found in cis with p.Leu541Pro (PMID: 10206579, 16103129, 19217903, 24509150), which is thought to result in a more severe phenotype than the p.Ala1038Val variant alone (PMID: 25712131). ClinVar contains an entry for this variant (Variation ID: 7894). Experimental studies have shown that this missense change has a mild effect on ATPase activity of the ABCA4 protein (PMID: 11017087, 16103129, 25712131). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000008348 SCV000028556 pathogenic Stargardt disease 1 2003-06-01 no assertion criteria provided literature only
OMIM RCV000008350 SCV000028558 pathogenic Cone-rod dystrophy 3 2003-06-01 no assertion criteria provided literature only
Retina International RCV000085549 SCV000117686 not provided not provided no assertion provided not provided
NIHR Bioresource Rare Diseases, University of Cambridge RCV000505109 SCV000598960 likely pathogenic Retinal dystrophy 2015-01-01 no assertion criteria provided research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000008348 SCV000598961 likely pathogenic Stargardt disease 1 2015-01-01 no assertion criteria provided research
Human Genetics - Radboudumc,Radboudumc RCV000008348 SCV000804578 likely pathogenic Stargardt disease 1 2016-09-01 no assertion criteria provided clinical testing
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787493 SCV000926459 pathogenic Stargardt disease 2018-04-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787494 SCV000926460 pathogenic Retinitis pigmentosa 2018-04-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787495 SCV000926461 pathogenic Macular dystrophy 2018-04-01 no assertion criteria provided research
Reproductive Health Research and Development,BGI Genomics RCV000008348 SCV001142302 pathogenic Stargardt disease 1 2020-01-06 no assertion criteria provided curation 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
Sharon lab,Hadassah-Hebrew University Medical Center RCV000787493 SCV001160853 likely pathogenic Stargardt disease 2019-06-23 no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.