ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.4873C>T (p.His1625Tyr) (rs1085307968)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489654 SCV000577749 likely pathogenic not provided 2015-06-01 criteria provided, single submitter clinical testing The H1625Y variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The H1625Y variant 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. The H1625Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other 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. In addition, missense variants in nearby residues and in the same codon (G1623S, W1624G, H1625Q, L1631P) have been reported in the Human Gene Mutation Database in association with Stargardt disease and Retinal dystrophy (Stenson et al., 2014), supporting the functional importance of this residue and this region of the protein. Finally, in silico splice prediction algorithms predict that this substitution creates a cryptic splice donor site upstream of the natural splice donor site in exon 35, but without altering the natural splice donor site. Therefore, this variant is a strong candidate for a pathogenic variant. However, the possibility that it is a benign variant cannot be excluded.

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