ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.4537dup (p.Gln1513fs) (rs281865377)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000085645 SCV000490378 pathogenic not provided 2016-08-08 criteria provided, single submitter clinical testing The c.4537dupC mutation in the ABCA4 gene has been previously reported in association with an ABCA4- related disorder (Briggs et al., 2001). This duplication causes a frameshift starting with codon Glutamine 1513, changes this amino acid to a Proline residue and creates a premature Stop codon at position 42 of the new reading frame, denoted p.Gln1513ProfsX42. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Broad Institute Rare Disease Group,Broad Institute RCV001004999 SCV001164557 pathogenic Cone-rod dystrophy 3 2018-12-03 criteria provided, single submitter research The heterozygous p.Gln1513ProfsTer42 variant in ABCA4 was identified by our study in the compound heterozygous state, with a likely pathogenic variant, in one individual with cone-rod dystrophy. The p.Gln1513ProfsTer42 variant in ABCA4 has not been previously reported in individuals with cone-rod dystrophy but has been identified in 0.004031% (6/148860) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs281865377). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 1513 and leads to a premature termination codon 42 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the ABCA4 gene is an established disease mechanism in autosomal recessive cone-rod dystrophy, and this is a loss of function variant. The presence of this variant in combination with a likely pathogenic variant and in an individual with cone-rod dystrophy increases the likelihood that the p.Gln1513ProfsTer42 variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for cone-rod dystrophy in an autosomal recessive manner based on the predicted impact of the variant and the presence of a likely pathogenic variant in trans. ACMG/AMP Criteria applied: PM2, PVS1, PM3_Supporting (Richards 2015).
Invitae RCV000085645 SCV001211638 pathogenic not provided 2020-01-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln1513Profs*42) in the ABCA4 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs281865377, ExAC 0.2%). This variant has been observed in several individuals affected with inherited retinal dystrophy (PMID: 28041643, 11527935). ClinVar contains an entry for this variant (Variation ID: 99292). Loss-of-function variants in ABCA4 are known to be pathogenic (PMID: 10958761, 24938718, 25312043, 26780318). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001074410 SCV001239992 pathogenic Retinal dystrophy 2019-08-11 criteria provided, single submitter clinical testing
Retina International RCV000085645 SCV000117784 not provided not provided no assertion provided not provided
Centre for Genomic Medicine, Manchester,Central Manchester University Hospitals RCV000210298 SCV000259088 likely pathogenic Stargardt disease 1 2015-01-22 no assertion criteria provided clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504708 SCV000598978 pathogenic Retinitis pigmentosa 2015-01-01 no assertion criteria provided research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504962 SCV000598979 likely pathogenic Macular dystrophy 2015-01-01 no assertion criteria provided research
Human Genetics - Radboudumc,Radboudumc RCV000678509 SCV000804579 pathogenic Retinitis pigmentosa 19 2016-09-01 no assertion criteria provided clinical testing
Sharon lab,Hadassah-Hebrew University Medical Center RCV001002828 SCV001160845 pathogenic Cone-rod degeneration 2019-06-23 no assertion criteria provided research

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