Submissions for variant NM_000350.3(ABCA4):c.288C>A (p.Asn96Lys)

dbSNP: rs886039297

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255898	SCV000321325	uncertain significance	not provided	2018-09-28	criteria provided, single submitter	clinical testing	The N96K missense variant has been reported previously in association with Stargardt disease (Stenirri et al., 2004). However, this variant has also been reported on the same allele (in cis) with the G1961E variant in four unrelated individuals (Burke et al., 2012; Nassisi et al., 2018). The N96K variant has also been observed at GeneDx in cis with the G1961E variant. The N96K variant is not observed in large population cohorts (Lek et al., 2016). The N96K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Two other missense variants at this codon (N96H and N96D) have also been reported in association with Stargardt disease (Papaioannou et al., 2000). In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000255898	SCV004293327	pathogenic	not provided	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 96 of the ABCA4 protein (p.Asn96Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Stargardt disease (PMID: 15192030, 19265867). ClinVar contains an entry for this variant (Variation ID: 265006). 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 with a positive predictive value of 95%. This variant disrupts the p.Asn96 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28355279, 29925512, 30093795). 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.
Clinical Genetics, Academic Medical Center	RCV000255898	SCV001924583	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000255898	SCV001951345	uncertain significance	not provided		no assertion criteria provided	clinical testing