Submissions for variant NM_000350.3(ABCA4):c.5572T>A (p.Tyr1858Asn)

gnomAD frequency: 0.00001  dbSNP: rs371489809

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000421632	SCV000511908	likely pathogenic	not provided	2015-05-07	criteria provided, single submitter	clinical testing	The Y1858N variant that is likely pathogenic in the ABCA4 gene has not been reported as a pathogenic variant nor as a benign polymorphism to our knowledge. The Y1858N was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI ESP Exome Sequencing Project. This variant has been seen at GeneDx in another patient referred for the Stargardt disease panel analysis. The Y1858N variant 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. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In addition, another missense variant, a non-conservative substitution, at this residue (Y1858D) has been reported in association with Stargardt disease (Oldani et al., 2012). Therefore, this variant is a strong candidate for a pathogenic variant; however, the possibility that it is a benign variant cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000421632	SCV001559205	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1858 of the ABCA4 protein (p.Tyr1858Asn). This variant is present in population databases (rs371489809, gnomAD 0.002%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 28446513; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 377406). 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%. For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center	RCV002289547	SCV002579835	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2021-12-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002480281	SCV002794130	likely pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2021-10-13	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV003224874	SCV003921098	likely pathogenic	Age related macular degeneration 2	2023-03-06	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PM1, PM3, PM5, PM2_SUP, PP3
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004816654	SCV005071207	likely pathogenic	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing