Submissions for variant NM_000350.3(ABCA4):c.4926C>G (p.Ser1642Arg)

gnomAD frequency: 0.00001  dbSNP: rs61753017

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000085685	SCV000511903	likely benign	not provided	2018-11-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23953153, 16917483, 28044389, 30093795, 11846518, 24713488, 19365591, 23982839, 29114839, 29186038, 30060493, 29925512, 30718709, 32619608)
Mendelics	RCV000986355	SCV001135338	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2019-05-28	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001075879	SCV001241520	uncertain significance	Retinal dystrophy	2019-08-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085685	SCV001374726	pathogenic	not provided	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 1642 of the ABCA4 protein (p.Ser1642Arg). This variant is present in population databases (rs61753017, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive Stargardt disease, commonly in cis with the pathogenic variant c.5044_5058del (p.Val1682_Val1686del). This variant has also been observed without p.Val1682_Val1686del in individuals with autosomal recessive Stargardt disease, and the evidence is sufficient to classify p.Ser1642Arg as Pathogenic in isolation, whether or not p.Val1682_Val1686del is present (PMID: 16917483, 19365591, 29114839, 29186038, 30060493, 30718709). 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: 99332). 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 not expected to disrupt ABCA4 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000085685	SCV001447935	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000986355	SCV002521749	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.56; 3Cnet: 0.86). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099332). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV005025164	SCV005658793	likely pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2024-03-22	criteria provided, single submitter	clinical testing
Retina International	RCV000085685	SCV000117825	not provided	not provided		no assertion provided	not provided
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787506	SCV000926472	likely pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	RCV000986355	SCV005047041	pathogenic	Severe early-childhood-onset retinal dystrophy		no assertion criteria provided	research