ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.1958G>A (p.Arg653His) (rs141823837)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484928 SCV000564521 likely pathogenic not provided 2014-06-19 criteria provided, single submitter clinical testing A novel R653H variant that is likely pathogenic was identified in the ABCA4 gene. The R653H variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The R653H variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in an external database.The R653H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Another missense variant at the same residue (R653C) has been reported in the Human Gene Mutation Database in association with Stargardt disease (Stenson et al., 2009), supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Blueprint Genetics RCV001075584 SCV001241211 pathogenic Retinal dystrophy 2019-01-11 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000484928 SCV001245784 pathogenic not provided 2017-07-01 criteria provided, single submitter clinical testing
Invitae RCV000484928 SCV001383104 pathogenic not provided 2019-09-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 653 of the ABCA4 protein (p.Arg653His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs141823837, ExAC 0.01%). This variant has been observed in individuals affected with Stargardt disease (PMID: 25346251, 29975949, Invitae). ClinVar contains an entry for this variant (Variation ID: 417982). 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. This variant disrupts the p.Arg653 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23776498, 28559085). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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