ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.428C>T (p.Pro143Leu)

gnomAD frequency: 0.00001  dbSNP: rs62646860
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000085626 SCV000701764 likely pathogenic not provided 2017-09-13 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV001195926 SCV001366350 likely pathogenic Age related macular degeneration 2 2019-09-05 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PP3,PP5.
Invitae RCV000085626 SCV001590828 pathogenic not provided 2024-01-19 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 143 of the ABCA4 protein (p.Pro143Leu). This variant is present in population databases (rs62646860, gnomAD 0.003%). This missense change has been observed in individuals with ABCA4-related conditions (PMID: 14517951, 25412400, 29178665, 29854428). ClinVar contains an entry for this variant (Variation ID: 99273). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003330431 SCV004037681 pathogenic Stargardt disease 2023-08-29 criteria provided, single submitter clinical testing Variant summary: ABCA4 c.428C>T (p.Pro143Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251456 control chromosomes. c.428C>T has been reported in the literature in multiple individuals affected with Stargardt Disease (e.g. Abed_2018, DelPozo_2022, Ibanez_2021, Jaakson_2003, Smaragda_2018) and Cone Dystrophy (Consugar_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25412400, 35119454, 33369172, 14517951, 29854428, 29178665).Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Retina International RCV000085626 SCV000117765 not provided not provided no assertion provided not provided

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