ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.5327C>T (p.Pro1776Leu) (rs1553187939)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497807 SCV000589532 likely pathogenic not provided 2016-08-16 criteria provided, single submitter clinical testing The P1776L variant has been published previously in association with ABCA4-related disorders (Briggs et al., 2001; Mandal et al., 2005; Yzer et al., 2007). The 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. P1776L 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 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.
Invitae RCV000497807 SCV001395963 pathogenic not provided 2019-07-12 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 1776 of the ABCA4 protein (p.Pro1776Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals and families with inherited retinal dystrophy and/or Stargardt disease (PMID: 17893657, 11527935). ClinVar contains an entry for this variant (Variation ID: 431947). 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. For these reasons, this variant has been classified as Pathogenic.

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