ClinVar Miner

Submissions for variant NM_000026.4(ADSL):c.421C>T (p.Arg141Trp)

gnomAD frequency: 0.00002  dbSNP: rs756210458
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186711 SCV000240277 likely pathogenic not provided 2022-12-16 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10090474, 16403972, 10958654, 31623504, 33648541, 20933180)
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000415081 SCV000492859 pathogenic Generalized myoclonic seizure; Progressive neurologic deterioration; Inability to walk; Difficulty standing; Severe global developmental delay 2015-06-22 criteria provided, single submitter clinical testing
Invitae RCV001049471 SCV001213520 pathogenic Adenylosuccinate lyase deficiency 2023-11-08 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 141 of the ADSL protein (p.Arg141Trp). This variant is present in population databases (rs756210458, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of adenylosuccinate lyase deficiency (PMID: 31623504, 33648541). 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: 204815). 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 ADSL protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Laboratoire Génétique Moléculaire, CHRU TOURS RCV000186711 SCV001760574 likely pathogenic not provided 2021-03-31 criteria provided, single submitter clinical testing

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