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

gnomAD frequency: 0.00001  dbSNP: rs1553187939

Total submissions: 3

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000497807	SCV001395963	pathogenic	not provided	2024-09-23	criteria provided, single submitter	clinical testing	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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 431947). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
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