Submissions for variant NM_000350.3(ABCA4):c.1937+1G>A

gnomAD frequency: 0.00003  dbSNP: rs61752401

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000408499	SCV000281838	pathogenic	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000085448	SCV000490368	pathogenic	not provided	2024-03-04	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 26720470, 12192456, 33261146, 32531858, 34758253, 10958763, 23882696, 23953153, 17982420, 29555955, 28118664, 29925512, 32141364, 33988224, 32307445, 31964843, 34321860, 36460718, 35120629, 35260635, 35076026, 24585425)
CeGaT Center for Human Genetics Tuebingen	RCV000085448	SCV001245785	pathogenic	not provided	2019-02-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085448	SCV001590410	pathogenic	not provided	2023-09-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 28118664). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 99104). This variant is also known as IVS13+1G>A. Disruption of this splice site has been observed in individuals with Stargardt disease (PMID: 10958763, 24585425, 28118664). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs61752401, gnomAD 0.004%). This sequence change affects a donor splice site in intron 13 of the ABCA4 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.
Genomics England Pilot Project, Genomics England	RCV001542645	SCV001760056	pathogenic	Retinitis pigmentosa 19		criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000085448	SCV002009251	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
3billion	RCV001542645	SCV002058209	pathogenic	Retinitis pigmentosa 19	2022-01-03	criteria provided, single submitter	clinical testing	Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000032, PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000099104, 3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Institute of Human Genetics, University Hospital Muenster	RCV004584346	SCV002578080	pathogenic	See cases	2021-12-16	criteria provided, single submitter	clinical testing	ACMG categories: PVS1,PM2,PM3,PP5
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000408499	SCV004810182	pathogenic	Severe early-childhood-onset retinal dystrophy	2024-04-04	criteria provided, single submitter	clinical testing
Retina International	RCV000085448	SCV000117585	not provided	not provided		no assertion provided	not provided
Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	RCV004558306	SCV005046939	pathogenic	Stargardt disease 3		no assertion criteria provided	research