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

gnomAD frequency: 0.00001  dbSNP: rs886046564

Total submissions: 3

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000483262	SCV001404751	pathogenic	not provided	2022-09-23	criteria provided, single submitter	clinical testing	This variant disrupts the p.Pro1511 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20647261, 24154662, 28559085). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 417992). This missense change has been observed in individuals with Stargardt disease (PMID: 22427542, 26780318, 29925512; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.06%). This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 1511 of the ABCA4 protein (p.Pro1511His).
Revvity Omics, Revvity	RCV000483262	SCV004238400	likely pathogenic	not provided	2023-01-19	criteria provided, single submitter	clinical testing