ClinVar Miner

Submissions for variant NM_000026.4(ADSL):c.421C>T (p.Arg141Trp) (rs756210458)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186711 SCV000240277 pathogenic not provided 2014-11-19 criteria provided, single submitter clinical testing p.Arg141Trp (CGG>TGG): c.421 C>T in exon 4 of the ADSL gene (NM_000026.2) The R141W missense mutation in the ADSL gene has been reported previously in an individual with severe infantile epileptic encephalopathy, severe intellectual disability, and immature gyration and reduced myelination on MRI who also had a second ADSL mutation on the other chromosome (Kohler et al., 1999; Marie et al., 1999). It 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 R141W mutation is a non-conservative amino acid substitution and occurs at a position that is highly conserved across species. The variant is found in EPILEPSY panel(s).
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415081 SCV000492859 pathogenic Generalized myoclonic seizures; Progressive neurologic deterioration; Inability to walk; Difficulty standing; Severe global developmental delay 2015-06-22 criteria provided, single submitter clinical testing
Invitae RCV001049471 SCV001213520 uncertain significance Adenylosuccinate lyase deficiency 2019-10-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 141 of the ADSL protein (p.Arg141Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs756210458, ExAC 0.003%). This variant has been observed in an individual affected with adenylosuccinate lyase deficiency (PMID: 10090474, 10958654). ClinVar contains an entry for this variant (Variation ID: 204815). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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