ClinVar Miner

Submissions for variant NM_000026.4(ADSL):c.1187G>A (p.Arg396His)

gnomAD frequency: 0.00001  dbSNP: rs763542069
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186690 SCV000240256 pathogenic not provided 2023-06-12 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect as this variant reduces ADSL enzyme activity (De Zoysa Ariyananda et al., 2009; Zikanova et al., 2010; De Zoysa Ariyananda et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21210713, 19405474, 30573755, 20127976, 12368987, 16839792, 32405461, 33648541)
Illumina Laboratory Services, Illumina RCV000779373 SCV000915974 likely pathogenic Adenylosuccinate lyase deficiency 2017-05-05 criteria provided, single submitter clinical testing The ADSL c.1187G>A (p.Arg396His) missense variant has been reported in two studies in a compound heterozygous state with other missense variants in two individuals with adenylosuccinase deficiency (Castro et al. 2002; Zikanova et al. 2010). One individual presented with intellectual disability while the other presented a neonatal fatal form of the disorder. Control data are unavailable for the p.Arg396His variant, which is reported at a frequency of 0.00012 in the Latino population of the Genome Aggregation Database. Functional studies using biochemical and biophysical techniques have shown the p.Arg396His variant to have low residual enzyme activity and increased thermal instability (Ariyananda et al. 2009; Zikanova et al. 2010; Ariyananda et al. 2011). Based on the clinical and functional evidence, the p.Arg396His variant is classified as likely pathogenic for adenylosuccinase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000779373 SCV001586969 pathogenic Adenylosuccinate lyase deficiency 2023-12-02 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 396 of the ADSL protein (p.Arg396His). This variant is present in population databases (rs763542069, gnomAD 0.01%). This missense change has been observed in individual(s) with adenylosuccinate lyase deficiency (PMID: 12368987, 16839792; Invitae). 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: 204796). 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%. Experimental studies have shown that this missense change affects ADSL function (PMID: 19405474, 20127976). This variant disrupts the p.Arg396 amino acid residue in ADSL. Other variant(s) that disrupt this residue have been observed in individuals with ADSL-related conditions (PMID: 17188615), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000779373 SCV002022320 pathogenic Adenylosuccinate lyase deficiency 2021-07-09 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000186690 SCV002563732 pathogenic not provided 2020-02-01 criteria provided, single submitter clinical testing

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