ClinVar Miner

Submissions for variant NM_000026.4(ADSL):c.1349C>G (p.Thr450Ser) (rs372895468)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186712 SCV000240278 pathogenic not provided 2015-01-14 criteria provided, single submitter clinical testing p.Thr450Ser (ACT>AGT): c.1349 C>G in exon 12 of the ADSL gene (NM_000026.2) The T450S mutation in the ADSL gene has been reported in an individual with adenylosuccinate lyase deficiency and moderate intellectual disability who had another disease-causing mutation (Race et al., 2000; Zikanova et al., 2010). Functional studies show that T450S has an intermediate affect, decreasing enzyme activity by approximately 50% (Race et al., 2000), and Zikanova et al. concluded that T450S creates a thermally unstable protein with high residual enzyme activity (2010). The T450S 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. This substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Other missense mutations in nearby residues (S447P, S448P, R452P) have been reported in association with ADSL deficiency, supporting the functional importance of this region of the protein. Therefore, T450S is considered a disease-causing mutation in the ADSL gene. The variant is found in EPILEPSYV2-1 panel(s).

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