Submissions for variant NM_000350.3(ABCA4):c.4253+5G>T

dbSNP: rs61750138

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000085620	SCV000511894	pathogenic	not provided	2024-03-28	criteria provided, single submitter	clinical testing	Published functional studies demonstrate significant aberrant splicing with skipping of exon 28 (PMID: 29162642); Not observed at significant frequency in large population cohorts (gnomAD); In-silico analysis is inconclusive as to whether the variant alters gene splicing; in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 25525159, 35120629, 31964843, 36284460, 22247458, 9666097, 9973280, 23499370, 24550365, 28041643, 32581362, 29162642)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085620	SCV001227605	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change falls in intron 28 of the ABCA4 gene. It does not directly change the encoded amino acid sequence of the ABCA4 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs61750138, gnomAD 0.0009%). This variant has been observed in individuals with Stargardt disease (PMID: 9973280, 28041643; Invitae). ClinVar contains an entry for this variant (Variation ID: 99267). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 29162642). This variant disrupts the c.4253+5G nucleotide in the ABCA4 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 10958763, 11385708, 28041643, 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.
Blueprint Genetics	RCV001073983	SCV001239549	pathogenic	Retinal dystrophy	2018-09-06	criteria provided, single submitter	clinical testing
Retina International	RCV000085620	SCV000117759	not provided	not provided		no assertion provided	not provided
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504676	SCV000598972	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2015-01-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004529889	SCV004729505	pathogenic	ABCA4-related disorder	2023-12-11	no assertion criteria provided	clinical testing	The ABCA4 c.4253+5G>T variant is predicted to interfere with splicing. This variant has been reported in individuals with Stargardt disease (Lewis et al. 1999. PubMed ID: 9973280; Supplemental data, Turro et al. 2020. PubMed ID: 32581362; Table S3, Suga et al. 2022. PubMed ID: 36284460). A functional study using a midigene splicing assay showed that this variant causes a significant decrease in correctly spliced mRNA (Sangermano et al. 2018. PubMed ID: 29162642). Alternate variants of this nucleotide and an adjacent nucleotide (c.4253+5G>A and c.4253+4C>T) have been reported in individuals with Stargardt disease (Rivera et al. 2000. PubMed ID: 10958763; Ozgul et al. 2004. PubMed ID: 15108289). This c.4253+5G>T variant has not been reported in a large population database, indicating this variant is rare. Given the evidence, we interpret this variant as pathogenic.