Submissions for variant NM_000350.3(ABCA4):c.3323G>A (p.Arg1108His)

gnomAD frequency: 0.00003  dbSNP: rs61750121

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085570	SCV001214614	pathogenic	not provided	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1108 of the ABCA4 protein (p.Arg1108His). This variant is present in population databases (rs61750121, gnomAD 0.004%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 11328725, 28559085, 29925512). 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: 99219). 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 expected to disrupt ABCA4 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg1108 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16703556, 19074458, 26092729, 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.
Blueprint Genetics	RCV001073697	SCV001239256	pathogenic	Retinal dystrophy	2017-04-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000085570	SCV001249464	pathogenic	not provided	2020-05-01	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003992183	SCV004809704	pathogenic	Severe early-childhood-onset retinal dystrophy	2024-04-04	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001073697	SCV005070077	likely pathogenic	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700403	SCV005203573	pathogenic	Stargardt disease	2024-07-15	criteria provided, single submitter	clinical testing	Variant summary: ABCA4 c.3323G>A (p.Arg1108His) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251338 control chromosomes (gnomAD). c.3323G>A has been reported in the literature in multiple individuals affected with Stargardt Disease (e.g. Riveiro-Alvarez_2013, Cornelis_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 23755871, 35120629). ClinVar contains an entry for this variant (Variation ID: 99219). Based on the evidence outlined above, the variant was classified as pathogenic.
Retina International	RCV000085570	SCV000117708	not provided	not provided		no assertion provided	not provided