ClinVar Miner

Submissions for variant NM_000350.2(ABCA4):c.2588G>C (rs76157638)

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Total submissions: 23
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000085494 SCV000226568 pathogenic not provided 2016-05-18 criteria provided, single submitter clinical testing
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000008328 SCV000281847 pathogenic Stargardt disease 1 2016-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000085494 SCV000321344 pathogenic not provided 2018-11-20 criteria provided, single submitter clinical testing The c.2588 G>C pathogenic variant in the ABCA4 gene has been published previously in association with multiple ocular disorders including age-related macular degeneration, retinitis pigmentosa, and Stargardt disease (Maugeri et al., 1999; Briggs et al., 2001; Gonzalez-Garay et al., 2013; Wang et al., 2014; Teussink et al., 2015). G863A is the most common allele among individuals with Stargardt disease in Northern Europe, representing roughly 20-30% of disease associated alleles (Maugeri et al., 1999). It is observed in 528/65218 (0.81%) alleles, as well as in two homozygous individuals, from individuals of European background, in the ExAC dataset (Lek et al., 2016). In vitro functional studies have demonstrated 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). In addition, 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). A recent study has proposed that G863A exhibits pathogenicity only when observed in cis with the common N1868I variant (Zernant et al., 2017). We interpret c.2588 G>C as a pathogenic variant.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415097 SCV000492965 uncertain significance Abnormal macular morphology; Peripheral neuropathy 2013-11-28 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000008329 SCV000538010 likely pathogenic Cone-rod dystrophy 3 2015-10-23 criteria provided, single submitter clinical testing 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
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000787486 SCV000711736 pathogenic Stargardt disease 2018-04-10 criteria provided, single submitter clinical testing 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.
Ambry Genetics RCV000623365 SCV000742856 uncertain significance Inborn genetic diseases 2014-09-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Mendelics RCV000008328 SCV001135352 uncertain significance Stargardt disease 1 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001000290 SCV001156938 likely pathogenic not specified 2019-04-18 criteria provided, single submitter clinical testing 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.
Invitae RCV000085494 SCV001211627 pathogenic not provided 2020-01-10 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 863 of the ABCA4 protein (p.Gly863Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs76157638, ExAC 0.8%), including multiple homozygous individuals. 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).
Blueprint Genetics RCV000505063 SCV001241506 pathogenic Retinal dystrophy 2019-08-09 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000085494 SCV001245777 pathogenic not provided 2019-07-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198385 SCV001369306 uncertain significance Abnormal retinal morphology; Abnormal macular morphology; Peripheral neuropathy 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. This variant was detected in heterozygous state.
OMIM RCV000008328 SCV000028536 pathogenic Stargardt disease 1 2008-07-01 no assertion criteria provided literature only
OMIM RCV000008329 SCV000028537 pathogenic Cone-rod dystrophy 3 2008-07-01 no assertion criteria provided literature only
Retina International RCV000085494 SCV000117631 not provided not provided no assertion provided not provided
NIHR Bioresource Rare Diseases, University of Cambridge RCV000505063 SCV000598951 likely pathogenic Retinal dystrophy 2015-01-01 no assertion criteria provided research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000008328 SCV000598952 likely pathogenic Stargardt disease 1 2015-01-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787486 SCV000926452 pathogenic Stargardt disease 2018-04-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787487 SCV000926453 pathogenic Retinitis pigmentosa 2018-04-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787768 SCV000926773 pathogenic Cone-rod dystrophy 2018-04-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000505063 SCV000926779 pathogenic Retinal dystrophy 2018-04-01 no assertion criteria provided research
Sharon lab,Hadassah-Hebrew University Medical Center RCV000787487 SCV001160859 likely pathogenic Retinitis pigmentosa 2019-06-23 no assertion criteria provided research

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