Submissions for variant NM_000350.3(ABCA4):c.6729+5_6729+19del

dbSNP: rs749526785

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497773	SCV000589300	likely pathogenic	not provided	2016-09-20	criteria provided, single submitter	clinical testing	The c.6729+5_6729+19del15 variant has been reported in association with ABCA4-related eye disorders (Littink et al., 2010; Fujinami et al. 2013; Duncker et al., 2015). Upon examining the phenotypes and ages-of-onset associated with different variants, it was observed that the c.6729+5_6729+19del15 variant is associated with a very early age-of-onset with the median age-of-onset being 5 years (Fakin et al., 2016). The c.6729+5_6729+19del15 variant was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. Several in-silico splice prediction models predict that c.6729+5_6729+19del15 either damages or destroys the natural donor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, based on the currently available information, it is a likely pathogenic variant.
Eurofins Ntd Llc (ga)	RCV000497773	SCV000700938	pathogenic	not provided	2017-05-23	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001074704	SCV001240297	pathogenic	Retinal dystrophy	2019-04-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000497773	SCV001392513	pathogenic	not provided	2024-10-24	criteria provided, single submitter	clinical testing	This sequence change falls in intron 48 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 (rs749526785, gnomAD 0.06%). This variant has been observed in individuals with bullseye maculopathy, autosomal recessive retinitis pigmentosa, retinal degeneration, cone-rod dystrophy, and Stargardt disease (PMID: 20554613, 25283059, 27583828, 28041643, 29925512). This variant is also known as c.6729+4del1. ClinVar contains an entry for this variant (Variation ID: 283573). 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). For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000497773	SCV001447679	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000497773	SCV001501905	pathogenic	not provided	2020-10-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002480011	SCV002798386	pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2024-04-11	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001074704	SCV005069999	pathogenic	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000416441	SCV000494173	pathogenic	Cone-rod dystrophy 3		no assertion criteria provided	research	This variant was identified as homozygous in an individual with cone rod dystrophy.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504933	SCV000599022	likely pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000678515	SCV000804587	uncertain significance	Retinitis pigmentosa 19	2016-09-01	no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV001542553	SCV001760040	likely pathogenic	Age related macular degeneration 2		no assertion criteria provided	clinical testing