ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.4532C>A (p.Pro1511His) (rs886046564)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483262 SCV000564535 likely pathogenic not provided 2013-06-11 criteria provided, single submitter clinical testing The P1511H missense change in the ABCA4 gene has not been reported as a pathogenic variant or as a benign polymorphism to our knowledge. The P1511H amino acid substitution is non-conservative with a neutral and non-polar residue (Pro) being replaced by a positively charged and polar residue (His). Furthermore, the loss of a Proline residue with its unique structure may affect the structure of the protein. The residue at which this substitution occurs is well conserved in the ABCR protein. According to the Human Gene Mutation Database (HGMD) other missense mutations (G1507W, G1508C, P1512R, P1512H, Q1513R, R1517S, L1525P) have been reported in nearby residues in association with ABCA4-related disorders (Stenson, 2009). The P1511H variant was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. Therefore, P1511H is a strong candidate for a pathogenic variant although the possibility that it is a benign polymorphism cannot be excluded.
Invitae RCV000483262 SCV001404751 uncertain significance not provided 2019-11-08 criteria provided, single submitter clinical testing This sequence change replaces proline with histidine at codon 1511 of the ABCA4 protein (p.Pro1511His). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Stargardt disease (PMID: 22427542, 29925512, 26780318). ClinVar contains an entry for this variant (Variation ID: 417992). 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.Pro1511 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been observed in individuals with ABCA4-related conditions (PMID: 20647261, 24154662, 28559085), which suggests that this may be a clinically significant amino acid residue. 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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