ClinVar Miner

Submissions for variant NM_000026.4(ADSL):c.907C>T (p.Arg303Cys)

gnomAD frequency: 0.00005  dbSNP: rs373458753
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000727198 SCV000343734 pathogenic not provided 2016-07-26 criteria provided, single submitter clinical testing
Invitae RCV000293106 SCV000826390 pathogenic Adenylosuccinate lyase deficiency 2024-01-06 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 303 of the ADSL protein (p.Arg303Cys). This variant is present in population databases (rs373458753, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of adenylosuccinate lyase deficiency (PMID: 3234432, 10090474, 10958654). ClinVar contains an entry for this variant (Variation ID: 289379). 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: 10958654, 20127976, 22812634, 23714113). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000293106 SCV003844214 pathogenic Adenylosuccinate lyase deficiency 2023-02-25 criteria provided, single submitter clinical testing Variant summary: ADSL c.907C>T (p.Arg303Cys) results in a non-conservative amino acid change located in the Fumarate lyase, N-terminal domain (IPR022761) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251476 control chromosomes (gnomAD). c.907C>T has been reported in the literature as a biallelic genotype in individuals affected with Adenylosuccinate Lyase Deficiency (e.g. Marie_1999, Race_2000, Zikanova_2010). These data indicate that the variant is likely to be associated with disease. Several publications indicate that the variant protein has reduced enzymatic activity for the conversion of S-AMP and SAICAR with recorded activity levels of 4.5-18% and 26-44% of wildtype, respectively (e.g. Race_2000, Zikanova_2010, Ray_2012). Two ClinVar submitters have assessed the variant since 2014: both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV000727198 SCV003924608 likely pathogenic not provided 2023-05-07 criteria provided, single submitter clinical testing Published functional studies demonstrate the variant results in a reduction in enzyme activity (Ray et al., 2013; Zikanova et al., 2010); 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: 36338215, 22812634, 20127976, 10090474, 10958654, 11783532, 3234432, 23714113, 22180458, 31440721)

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