ClinVar Miner

Submissions for variant NM_000026.4(ADSL):c.736A>G (p.Lys246Glu)

gnomAD frequency: 0.00003  dbSNP: rs119450944
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000002570 SCV000631370 pathogenic Adenylosuccinate lyase deficiency 2023-04-28 criteria provided, single submitter clinical testing Experimental studies have shown that this missense change affects ADSL function (PMID: 19405474). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 2466). This missense change has been observed in individual(s) with adenylosuccinate lyase deficiency (PMID: 1405483, 10090474, 27504266). This variant is present in population databases (rs119450944, gnomAD 0.006%). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 246 of the ADSL protein (p.Lys246Glu).
Revvity Omics, Revvity RCV000002570 SCV002021315 likely pathogenic Adenylosuccinate lyase deficiency 2021-04-23 criteria provided, single submitter clinical testing
GeneDx RCV002280090 SCV002568547 likely pathogenic not provided 2022-04-14 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); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 1405483, 27504266, 21210713, 10888601, 23055421, 10090474, 19405474, 31440721)
PreventionGenetics, part of Exact Sciences RCV003398421 SCV004120673 pathogenic ADSL-related disorder 2023-08-10 criteria provided, single submitter clinical testing The ADSL c.736A>G variant is predicted to result in the amino acid substitution p.Lys246Glu. This variant was reported in the compound heterozygous state in three patients with adenylosuccinate lyase deficiency (Marie. 1999. PubMed ID: 10090474; Donti. 2016. PubMed ID: 27504266). Functional in vitro assays demonstrated this variant impairs enzyme kinetics and the ability to properly form a tetramer (Ariyananda. 2009. PubMed ID: 19405474). This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD ( This variant is interpreted as pathogenic.
OMIM RCV000002570 SCV000022728 pathogenic Adenylosuccinate lyase deficiency 1999-01-01 no assertion criteria provided literature only

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