ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.6119G>A (p.Arg2040Gln) (rs148460146)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000132592 SCV000490382 likely pathogenic not provided 2016-12-06 criteria provided, single submitter clinical testing The R2040Q variant has been published previously in association with ABCA4-related disorders (Westeneng-van Haaften et al., 2012; Zernant et al., 2014; Zaneveld et al., 2015). The 1000 Genomes Project Consortium reports it was observed in 5/1008 (0.5%) alleles from individuals of East Asian background, indicating it may be a rare variant in this population. R2040Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position within a nucleotide-binding domain that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic.
Mendelics RCV000986347 SCV001135325 likely pathogenic Stargardt disease 1 2020-01-31 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001073482 SCV001239025 pathogenic Retinal dystrophy 2019-03-29 criteria provided, single submitter clinical testing
Invitae RCV000132592 SCV001374374 uncertain significance not provided 2019-11-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 2040 of the ABCA4 protein (p.Arg2040Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs148460146, ExAC 0.2%). This variant has been observed with other ABCA4 variants in individuals affected with Stargardt disease (PMID: 26780318, 25066811, 25474345, 22449572). ClinVar contains an entry for this variant (Variation ID: 143076). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Department of Ophthalmology and Visual Sciences Kyoto University RCV000132592 SCV000172537 probable-non-pathogenic not provided no assertion criteria provided not provided Converted during submission to Likely benign.
Genomics England Pilot Project,Genomics England RCV001542554 SCV001760042 likely pathogenic Retinitis pigmentosa 19 no assertion criteria provided clinical testing

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