ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.4919G>A (p.Arg1640Gln) (rs61751403)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000321118 SCV000281908 pathogenic Stargardt disease 1 2016-01-01 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000085684 SCV000336550 pathogenic not provided 2015-10-27 criteria provided, single submitter clinical testing
GeneDx RCV000085684 SCV000511902 pathogenic not provided 2017-02-23 criteria provided, single submitter clinical testing The R1640Q variant in the ABCA4 gene has been reported previously in both the homozygous and compound hetereozygous state in association with Stargardt disease and cone-rod dystrophy (Briggs et al., 2001; Boulanger-Scemama et al., 2015; Simonelli et al., 2000; Riveiro-Alvarez et al., 2013).The R1640Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1640Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In addition, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant at this same codon (R1640W), as well as missense variants in neighboring codons (A1637T, S1642R) have been reported in the Human Gene Mutation Database in association with Stargardt disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R1640Q as a pathogenic variant.
Invitae RCV000085684 SCV001198188 pathogenic not provided 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1640 of the ABCA4 protein (p.Arg1640Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs61751403, ExAC 0.03%). This variant has been observed in individuals and families affected with Stargardt disease or cone-rod dystrophy (PMID: 11527935, 26103963, 23755871, 10711710). ClinVar contains an entry for this variant (Variation ID: 99331). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Studies have shown that this variant is associated with altered splicing, but the impact on the resulting protein product is unknown (PMID: 28118664). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV000504816 SCV001239057 pathogenic Retinal dystrophy 2019-04-25 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000085684 SCV001334599 pathogenic not provided 2020-02-01 criteria provided, single submitter clinical testing
Institute of Medical Molecular Genetics, University of Zurich RCV000321118 SCV001548083 likely pathogenic Stargardt disease 1 2021-01-30 criteria provided, single submitter clinical testing
Retina International RCV000085684 SCV000117824 not provided not provided no assertion provided not provided
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504816 SCV000598987 uncertain significance Retinal dystrophy 2015-01-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787505 SCV000926471 pathogenic Stargardt disease 2018-04-01 no assertion criteria provided research
Sharon lab,Hadassah-Hebrew University Medical Center RCV000787505 SCV001160838 pathogenic Stargardt disease 2019-06-23 no assertion criteria provided research

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