ClinVar Miner

Submissions for variant NM_000026.4(ADSL):c.1264G>T (p.Asp422Tyr)

gnomAD frequency: 0.00002  dbSNP: rs119450943
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000002568 SCV000438686 uncertain significance Adenylosuccinate lyase deficiency 2017-04-27 criteria provided, single submitter clinical testing The ADSL c.1264G>T (p.Asp422Tyr) variant has been reported in one individual who suffered from severe psychomotor delay and had ADSL enzyme activity at approximately 30% of the normal value. The individual was found to be compound heterozygous for the p.Asp422Tyr variant and a second missense variant (Verginelli et al. 1998). Her asymptomatic mother was heterozygous for the p.Asp422Tyr variant. Control data are unavailable for the p.Asp422Tyr variant which is reported at a frequency of 0.00006 in the South Asian population of the Exome Aggregation Consortium but this is based on only one allele in a region of good sequence coverage so the variant is presumed to be rare. Functional studies demonstrated that the p.Asp422Tyr variant resulted in normal substrate affinity but decreased thermal stability, and that the structure of the protein appears to be compromised. The inactivation of the defective enzyme by HNE, a major product of membrane peroxidation, was suggested to account for the neurological defects noted in individuals with adenylosuccinase deficiency (Salerno et al. 2004; Crifo et al. 2005). The evidence for this variant is limited. The p.Asp422Tyr variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for adenylosuccinase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Neuberg Centre For Genomic Medicine, NCGM RCV000002568 SCV004101553 pathogenic Adenylosuccinate lyase deficiency criteria provided, single submitter clinical testing The missense variant c.1264G>T (p.Asp422Tyr) in ADSL gene has been reported in heterozygous state in individuals affected with Adenylosuccinase deficiency (Van Laer et al., 2018). Experimental studies have shown that this missense decrease in enzymatic activity of this mutant can be directly related to its reduced stability (Van Laer et al., 2018). This variant has allele frequency 0.001% in the gnomAD and novel in 1000 genome database. This variant has been reported to the ClinVar database as Uncertain significance. The amino acid Asp at position 422 is changed to a Tyr changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Asp422Tyr in ADSL is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000002568 SCV000022726 pathogenic Adenylosuccinate lyase deficiency 1998-02-27 no assertion criteria provided literature only

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