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

gnomAD frequency: 0.00178  dbSNP: rs61751374

Total submissions: 36

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000085549	SCV000511890	pathogenic	not provided	2024-06-21	criteria provided, single submitter	clinical testing	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)
CeGaT Center for Human Genetics Tuebingen	RCV000085549	SCV000692634	pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	ABCA4: PM3:Very Strong, PM1, PM2:Supporting, PS3:Supporting, BP4
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000787493	SCV000711770	likely pathogenic	Stargardt disease	2024-02-21	criteria provided, single submitter	clinical testing	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.
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; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2021-12-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778259	SCV000914431	pathogenic	ABCA4-related disorder	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	Age related macular degeneration 2	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085549	SCV001417577	pathogenic	not provided	2024-01-26	criteria provided, single submitter	clinical testing	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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000008350	SCV001440313	pathogenic	Cone-rod dystrophy 3	2019-01-01	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000085549	SCV001447775	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000008348	SCV001573325	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2021-04-08	criteria provided, single submitter	research	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.
Revvity Omics, Revvity	RCV000085549	SCV002018103	pathogenic	not provided	2023-12-14	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000787495	SCV002044408	likely pathogenic	Macular dystrophy	2021-11-22	criteria provided, single submitter	clinical testing	_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
Institute of Human Genetics, University Hospital Muenster	RCV000008348	SCV002496134	pathogenic	Severe early-childhood-onset retinal dystrophy	2019-01-08	criteria provided, single submitter	clinical testing	ACMG categories: PS1,PS3,PP2,PP3,PP5
Mendelics	RCV001196125	SCV002517486	pathogenic	Age related macular degeneration 2	2022-05-04	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000008348	SCV002581780	pathogenic	Severe early-childhood-onset retinal dystrophy	2022-08-11	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000505109	SCV002761442	pathogenic	Retinal dystrophy	2021-02-25	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000008348	SCV002769511	pathogenic	Severe early-childhood-onset retinal dystrophy	2021-05-06	criteria provided, single submitter	clinical testing	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
Institute of Human Genetics, University of Leipzig Medical Center	RCV000008348	SCV003804643	pathogenic	Severe early-childhood-onset retinal dystrophy	2023-01-31	criteria provided, single submitter	clinical testing	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
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000085549	SCV005199083	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
OMIM	RCV000008348	SCV000028556	pathogenic	Severe early-childhood-onset retinal dystrophy	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	Severe early-childhood-onset retinal dystrophy	2015-01-01	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000008348	SCV000804578	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2016-09-01	no assertion criteria provided	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787493	SCV000926459	pathogenic	Stargardt disease	2018-04-01	no assertion criteria provided	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787494	SCV000926460	pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787495	SCV000926461	pathogenic	Macular dystrophy	2018-04-01	no assertion criteria provided	research
Reproductive Health Research and Development, BGI Genomics	RCV000008348	SCV001142302	pathogenic	Severe early-childhood-onset retinal dystrophy	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
PreventionGenetics, part of Exact Sciences	RCV000778259	SCV004116214	pathogenic	ABCA4-related disorder	2024-08-27	no assertion criteria provided	clinical testing	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.
Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	RCV000008348	SCV005046997	likely pathogenic	Severe early-childhood-onset retinal dystrophy		no assertion criteria provided	research