Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000186692 | SCV000240258 | pathogenic | not provided | 2012-07-19 | criteria provided, single submitter | clinical testing | p.Arg426Cys (CGT>TGT): c.1276 C>T in exon 12 of the ADSL gene (NM_000026.2) The Arg426Cys mutation is a non-conservative amino acid change, since a positively charged Arginine is replaced with a neutral Cysteine, which may also affect formation of disulfide bonds. Although this specific mutation has not been published previously to our knowledge, a different missense substitution at the same position, Arg426His, is the most commonly observed mutation in ADSL and has been reported in homozygous as well as compound heterozgous form (Jurecka et al., 2008; Marie et al., 1999; Zikanova et al. 2010). The Arg426His mutation is located at the surface of the substrate channel of the encoded protein where its presence disrupts arginine-mediated interactions with Gln409 and Asp422 residues. Functional studies have demonstrated that Arg426His significantly reduces enzyme activity and thermal stability (Zikanova et al. 2010). The variant is found in CHILD-EPI panel(s). |
| Clinical Genomics Program, |
RCV001253786 | SCV001427090 | uncertain significance | Adenylosuccinate lyase deficiency | 2019-10-18 | no assertion criteria provided | clinical testing | The p.Arg426Cys variant in the ADSL gene has not been previously reported in association with disease. This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Notably, a different amino acid change (p.Arg426His) has been previously reported at this residue. The p.Arg426His variant is classified as pathogenic and is the most commonly observed variant associated with adenylosuccinase deficiency (Jurecka et al., 2015), which suggests another change at this residue, such as p.Arg426Cys, may similarly disrupt protein function. Computational tools predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Arg426Cys variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2, PM5, PP3] |