ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs1553187939
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Total submissions: 3
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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 2022-07-12 criteria provided, single submitter clinical testing This missense change has been observed in individual(s) with inherited retinal dystrophy and/or Stargardt disease (PMID: 11527935, 17893657). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1776 of the ABCA4 protein (p.Pro1776Leu). ClinVar contains an entry for this variant (Variation ID: 431947). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA4 protein function.
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel RCV003324528 SCV004030352 pathogenic Stargardt disease 2023-07-24 criteria provided, single submitter research Clinical significance based on ACMG v2.0

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