Submissions for variant NM_000350.3(ABCA4):c.4773+3A>G

gnomAD frequency: 0.00004  dbSNP: rs759672616

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000408554	SCV000281905	pathogenic	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000425309	SCV000511900	pathogenic	not provided	2015-09-03	criteria provided, single submitter	clinical testing	The c.4773+3 A>G splice site variant in the ABCA4 gene has been previously reported in association with Stargardt disease (Duno et al., 2012; Jonsson et al., 2013; Braun et al., 2013). This variant is predicted to destroy the canonical splice donor site in intron 33. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.4773+3 A>G variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000425309	SCV001227047	pathogenic	not provided	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change falls in intron 33 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 (rs759672616, gnomAD 0.02%). This variant has been observed in individual(s) with clinical features of ABCA4-related conditions (PMID: 23443024, 23918662, 29555955, 30718709). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 236122). 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: 28118664, 29162642). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV000787761	SCV001241368	pathogenic	Retinal dystrophy	2019-05-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000425309	SCV001248239	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000425309	SCV001446942	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000425309	SCV002019710	pathogenic	not provided	2020-09-28	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000408554	SCV002102455	pathogenic	Severe early-childhood-onset retinal dystrophy	2022-02-18	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PM3_VSTR, PS3, PM2_SUP
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787761	SCV000926766	uncertain significance	Retinal dystrophy	2018-04-01	no assertion criteria provided	research