Submissions for variant NM_000350.3(ABCA4):c.4773G>T (p.Gly1591=)

gnomAD frequency: 0.00003  dbSNP: rs751844313

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV001075350	SCV001240971	likely pathogenic	Retinal dystrophy	2018-05-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001340257	SCV001534058	pathogenic	not provided	2024-10-07	criteria provided, single submitter	clinical testing	This sequence change affects codon 1591 of the ABCA4 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ABCA4 protein. This variant also falls at the last nucleotide of exon 33, which is part of the consensus splice site for this exon. This variant is present in population databases (rs751844313, gnomAD 0.02%). This variant has been observed in individuals with clinical features of Stargardt disease (internal data). ClinVar contains an entry for this variant (Variation ID: 866944). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.4773G nucleotide in the ABCA4 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 23982839, 24677105, 29162642). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017784	SCV004847443	likely pathogenic	Stargardt disease	2024-02-12	criteria provided, single submitter	clinical testing	The p.Gly1591Gly (c.4773G>T) variant in ABCA4 has been reported in the compound heterozygous state in 3 individuals with Stargardt disease (Invitae pers. comm.). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 866944). It was absent from large population studies (gnomAD v.3.2.1.). Although this silent variant does not alter an amino acid residue, it is located in the last base of the exon, which is part of the 5’ splice region. Computational tools suggest an impact to splicing. A different variant at the same nucleotide position (c.4773G>C, p.Gly1591Gly) has been reported in the compound heterozygous state with other disease causing variants in ABCA4 in at least 2 individuals with Stargardt disease (Fujinami 2013 PMID: 23982839; Burke 2014 PMID: 24677105). Additionally, in vitro functional mini-gene splicing studies have shown that the c.4773G>C change causes aberrant splicing with no correctly spliced mRNA that leads to skipping of exon 33 and results in a premature stop codon (Sangermano 2018 PMID: 29162642), suggesting that variants at this position are likely to disrupt RNA splicing. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Stargardt disease. ACMG/AMP Criteria applied: PM3, PS3_Moderate, PM2_Supporting, PP3.
Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	RCV004564577	SCV005047023	likely pathogenic	Severe early-childhood-onset retinal dystrophy		no assertion criteria provided	research
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001075350	SCV005072238	likely pathogenic	Retinal dystrophy	2018-01-01	no assertion criteria provided	clinical testing