ClinVar Miner

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

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Total submissions: 2
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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.
Invitae RCV000489654 SCV001376497 uncertain significance not provided 2019-10-29 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 1625 of the ABCA4 protein (p.His1625Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with inherited retinal dystrophy (PMID: 27353947, 29555955). ClinVar contains an entry for this variant (Variation ID: 427117). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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