ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.4457C>T (p.Pro1486Leu) (rs61750145)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000408536 SCV000281890 likely pathogenic Stargardt disease 1 2016-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000085636 SCV000511897 pathogenic not provided 2016-11-18 criteria provided, single submitter clinical testing The P1486L variant has been published as a homozygous variant and as a compound heterozygous variant in association with ABCA4-related disorders (Downes et al., 2012; Briggs et al., 2001). The P1486L variant has been observed at GeneDx with other pathogenic variants. The P1486L 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. The P1486L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is pathogenic.
Mendelics RCV000408536 SCV001135340 pathogenic Stargardt disease 1 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV000085636 SCV001205168 pathogenic not provided 2020-08-29 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 1486 of the ABCA4 protein (p.Pro1486Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs61750145, ExAC 0.1%). This variant has been observed in individual(s) with Stargardt disease (PMID: 28559085, 30093795, 22247458, 23755871) as well as cone-rod dystrophy (PMID: 18285826). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99283). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001074852 SCV001240453 pathogenic Retinal dystrophy 2019-07-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000085636 SCV001248245 pathogenic not provided 2016-11-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198562 SCV001369551 pathogenic Age-related macular degeneration 2 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000085636 SCV001448014 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Baylor Genetics RCV000408536 SCV001521356 likely pathogenic Stargardt disease 1 2020-08-01 criteria provided, single submitter clinical testing This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Retina International RCV000085636 SCV000117775 not provided not provided no assertion provided not provided
Sharon lab,Hadassah-Hebrew University Medical Center RCV001002829 SCV001160846 pathogenic Stargardt disease 2019-06-23 no assertion criteria provided research

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