ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.5714+5G>A (rs61751407)

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Total submissions: 26
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000210321 SCV000281936 pathogenic Stargardt disease 1 2016-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000085757 SCV000321355 pathogenic not provided 2018-09-06 criteria provided, single submitter clinical testing The c.5714+5G>A variant in the ABCA4 gene has been reported previously in the compound heterozygous state, in trans with a second ABCA4 pathogenic variant, in individuals with Stargardt disease and cone rod dystrophy (Cremers et al., 1998; Cideciyan et al., 2009; Zernant et al., 2011). This variant reduces the quality of the splice donor site in intron 40, and is expected to cause abnormal gene splicing. The variant is observed in 69/126596 (0.055%) alleles from individuals of European (Non-Finnish) background in large population cohorts (Lek et al., 2016). Another splice site variant at the same position (c.5714+5G>T ) has been reported in the Human Gene Mutation Database in association with Stargardt disease (Stenson et al., 2014). Therefore, we interpret c.5714+5G>A as a pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000085757 SCV000341399 pathogenic not provided 2016-05-11 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778997 SCV000915438 pathogenic ABCA4-Related Disorders 2018-09-07 criteria provided, single submitter clinical testing Across a selection of the available literature, the ABCA4 c.5714+5G>A variant, also referred to as IVS40+5G>A, has been identified in 26 individuals with Stargardt disease, including in one homozygote, 20 compound heterozygotes, and five heterozygotes in whom a second variant was not identified, and in six compound heterozygotes with cone-rod dystrophy (Cremers et al. 1998; Rivera et al. 2000; Gerth et al. 2002; Hargitai et al. 2005; Hwang et al. 2009; Cideciyan et al. 2009). The variant was also found in four unaffected family members in a heterozygous state. The variant was absent from 320 control individuals, but is reported at a frequency of 0.00151 in the European American population of the Exome Sequencing Project. RT-PCR analysis of transformed COS-7 cells revealed that the c.5714+5G>A variant generates both a correctly spliced and an incorrectly spliced product, suggesting aberrant splicing with a possibility of some residual activity of the ABCA4 protein (Rivera et al. 2000). Based on the collective evidence, the c.5714+5G>A variant is classified as pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Mendelics RCV000210321 SCV001135329 pathogenic Stargardt disease 1 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV000085757 SCV001217350 pathogenic not provided 2019-12-26 criteria provided, single submitter clinical testing This sequence change falls in intron 40 of the ABCA4 gene. It does not directly change the encoded amino acid sequence of the ABCA4 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs61751407, ExAC 0.06%). This variant has been reported to segregate with autosomal recessive Stargardt disease and cone-rod dystrophy in multiple families and individuals (PMID: 9466990, 10413692, 19074458). ClinVar contains an entry for this variant (Variation ID: 99403). Nucleotide substitutions within the consensus splice site are relatively common causes 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, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001074898 SCV001240502 pathogenic Retinal dystrophy 2019-08-16 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000085757 SCV001247603 pathogenic not provided 2019-09-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000515694 SCV001365627 pathogenic Stargardt disease 2019-05-08 criteria provided, single submitter clinical testing The c.5714+5G>A variant in ABCA4 is one of the most common variants in ABCA4 in patients with autosomal recessive Stargardt disease, accounting for up to 16% of disease-causing variants in this gene (Cremers 1998, River 2000, Smaragda 2018, Birtel 2018). It has also been identified in 71/129064 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 99403). This variant is located in the 5' splice region, and in vitro functional studies support an impact on protein function (Rivera 2000, Sangermano 2018). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Stargardt disease. ACMG/AMP Criteria applied: PM3_VeryStrong, PVS1_Strong, PP1.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001195977 SCV001366404 pathogenic Abnormal electroretinogram; Retinal degeneration; Cone/cone-rod dystrophy; Photophobia; Monochromacy 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS3,PM3,PP4,PP5. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196124 SCV001366611 pathogenic Hypermetropia; Reduced visual acuity; Granular macular appearance 2019-03-23 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP2. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196399 SCV001367006 pathogenic Abnormal electroretinogram; Macular dystrophy 2019-11-12 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197077 SCV001367712 pathogenic Visual impairment 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP2,PP3,PP5. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198135 SCV001368966 pathogenic Abnormal electroretinogram; Macular degeneration 2019-06-04 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,BP4. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198561 SCV001369550 pathogenic Telecanthus; Blepharophimosis; Atrial septal defect; Micrognathia; Aggressive behavior; Abnormal facial shape; Premature birth; Posterior embryotoxon; Oligodontia; Restlessness; Intrauterine growth retardation; Postnatal growth retardation 2019-12-02 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PP3,PP2,PM3,PS1. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198726 SCV001369721 pathogenic Visual impairment; Hypermetropia; Chorioretinal dystrophy; Severe visual impairment; Macular dystrophy 2019-12-04 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3. This variant was detected in heterozygous state.
OMIM RCV000332324 SCV000028553 pathogenic Cone-rod dystrophy 3 2008-07-01 no assertion criteria provided literature only
Retina International RCV000085757 SCV000117898 not provided not provided no assertion provided not provided
Centre for Genomic Medicine, Manchester,Central Manchester University Hospitals RCV000210303 SCV000259077 pathogenic Retinitis pigmentosa 19 2015-01-23 no assertion criteria provided clinical testing
Centre for Genomic Medicine, Manchester,Central Manchester University Hospitals RCV000210321 SCV000259089 pathogenic Stargardt disease 1 2015-01-22 no assertion criteria provided clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000332324 SCV000536750 pathogenic Cone-rod dystrophy 3 2015-07-23 no assertion criteria provided research
Rui Chen Lab,Baylor College of Medicine RCV000515694 SCV000579418 pathogenic Stargardt disease 2017-05-09 no assertion criteria provided research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000210321 SCV000599001 likely pathogenic Stargardt disease 1 2015-01-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000515694 SCV000926481 likely pathogenic Stargardt disease 2018-04-01 no assertion criteria provided research
GenomeConnect, ClinGen RCV000845081 SCV000986928 not provided Stargardt disease; Cone-rod dystrophy no assertion provided phenotyping only Variant interpretted as pathogenic and reported on 07/26/2017 by GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Sharon lab,Hadassah-Hebrew University Medical Center RCV000515694 SCV001160825 pathogenic Stargardt disease 2019-06-23 no assertion criteria provided research

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