Submissions for variant NM_000350.3(ABCA4):c.185C>T (p.Pro62Leu)

gnomAD frequency: 0.00001  dbSNP: rs1057520211

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000417747	SCV000511879	uncertain significance	not provided	2013-06-10	criteria provided, single submitter	clinical testing	The P62L missense change has not been reported as a pathogenic variant or as a benign polymorphism to our knowledge. The P62L amino acid substitution is semi-conservative as Proline and Leucine are both neutral and non-polar residues. However, 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, other missense mutations (N58K, G65E, P68R) have been reported in nearby residues (Stenson et al., 2009). A different missense variant at this codon (P62S) has been reported in association with an ABCA4-related disorder (Zernant et al., 2011). The P62L 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. Therefore, the P62L missense change is a candidate for a pathogenic variant, although the possibility that it is a benign polymorphism cannot be completely excluded.
Blueprint Genetics	RCV001075540	SCV001241166	uncertain significance	Retinal dystrophy	2018-12-19	criteria provided, single submitter	clinical testing
Invitae	RCV000417747	SCV002315647	likely pathogenic	not provided	2021-08-19	criteria provided, single submitter	clinical testing	This sequence change replaces proline with leucine at codon 62 of the ABCA4 protein (p.Pro62Leu). 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 individual(s) with clinical features of Stargardt disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 377400). 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. This variant disrupts the p.Pro62 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been observed in individuals with ABCA4-related conditions (PMID: 21911583, 32036094; Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.