ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.6229C>T (p.Arg2077Trp) (rs61750645)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000402409 SCV000281951 likely pathogenic Stargardt disease 1 2016-01-01 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000085797 SCV000336497 pathogenic not provided 2015-10-21 criteria provided, single submitter clinical testing
GeneDx RCV000085797 SCV000490383 pathogenic not provided 2015-06-22 criteria provided, single submitter clinical testing The R2077W missense variant in the ABCA4 gene has been reported previously in association with Stargardt disease and autosomal recessive cone-rod dystrophy (Lewis, 1999; Sun, 2000; Rivera, 2000; Kitiratschky, 2008). R2077W was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret R2077W as a pathogenic variant.
Broad Institute Rare Disease Group,Broad Institute RCV001004998 SCV001164556 likely pathogenic Cone-rod dystrophy 3 2018-12-03 criteria provided, single submitter research The heterozygous p.Arg2077Trp variant in ABCA4 was identified by our study in the compound heterozygous state, with a pathogenic variant, in one individual with cone-rod dystrophy. The presence of this variant in combination with a likely pathogenic variant and in an individual with cone-rod dystrophy increases the likelihood that the p.Arg2077Trp variant is pathogenic. This variant has been identified in 0.0004062% (1/246206) of chromosomes and by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs61750645). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with an additional reported pathogenic variant (ClinVar Variation ID: 7904) and a reported likely pathogenic variant (ClinVar Variation ID: 99224) in two individuals with ABCA4-related disease reported in the literature increases the likelihood that the p.Arg2077Trp variant is pathogenic (PMID: 23755871, 18285826). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PM3_Strong (Richards 2015).
Invitae RCV000085797 SCV001205032 pathogenic not provided 2020-01-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 2077 of the ABCA4 protein (p.Arg2077Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Stargardt disease in families (PMID: 28559085). ClinVar contains an entry for this variant (Variation ID: 99438). This variant has been reported to affect ABCA4 protein function (PMID: 29847635). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV000504630 SCV001239102 pathogenic Retinal dystrophy 2019-06-15 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000085797 SCV001247596 pathogenic not provided 2017-11-01 criteria provided, single submitter clinical testing
Retina International RCV000085797 SCV000117940 not provided not provided no assertion provided not provided
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504630 SCV000599012 likely pathogenic Retinal dystrophy 2015-01-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787519 SCV000926487 likely pathogenic Stargardt disease 2018-04-01 no assertion criteria provided research

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