Submissions for variant NM_000350.3(ABCA4):c.6416G>C (p.Arg2139Pro)

dbSNP: rs761867791

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000264727	SCV000359195	uncertain significance	Retinitis Pigmentosa, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000319805	SCV000359196	uncertain significance	Macular degeneration	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000374572	SCV000359197	uncertain significance	Cone-Rod Dystrophy, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000280073	SCV000359198	uncertain significance	Stargardt Disease, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001099678	SCV001256150	uncertain significance	ABCA4-related disorder	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001380600	SCV001578717	pathogenic	not provided	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 2139 of the ABCA4 protein (p.Arg2139Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of inherited retinal dystrophy (PMID: 25472526, 28559085; internal data). 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: 298222). 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.Arg2139 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). 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.