ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.4926C>G (p.Ser1642Arg)

gnomAD frequency: 0.00001  dbSNP: rs61753017
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000085685 SCV000511903 likely benign not provided 2018-11-26 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23953153, 16917483, 28044389, 30093795, 11846518, 24713488, 19365591, 23982839, 29114839, 29186038, 30060493, 29925512, 30718709, 32619608)
Mendelics RCV000986355 SCV001135338 likely pathogenic Severe early-childhood-onset retinal dystrophy 2019-05-28 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001075879 SCV001241520 uncertain significance Retinal dystrophy 2019-08-15 criteria provided, single submitter clinical testing
Invitae RCV000085685 SCV001374726 pathogenic not provided 2024-01-08 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 1642 of the ABCA4 protein (p.Ser1642Arg). This variant is present in population databases (rs61753017, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive Stargardt disease, commonly in cis with the pathogenic variant c.5044_5058del (p.Val1682_Val1686del). This variant has also been observed without p.Val1682_Val1686del in individuals with autosomal recessive Stargardt disease, and the evidence is sufficient to classify p.Ser1642Arg as Pathogenic in isolation, whether or not p.Val1682_Val1686del is present (PMID: 16917483, 19365591, 29114839, 29186038, 30060493, 30718709). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99332). 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 not expected to disrupt ABCA4 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000085685 SCV001447935 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
3billion RCV000986355 SCV002521749 likely pathogenic Severe early-childhood-onset retinal dystrophy 2022-05-22 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.56; 3Cnet: 0.86). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099332). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Retina International RCV000085685 SCV000117825 not provided not provided no assertion provided not provided
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet RCV000787506 SCV000926472 likely pathogenic Retinitis pigmentosa 2018-04-01 no assertion criteria provided research

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