ClinVar Miner

Submissions for variant NM_054012.4(ASS1):c.349G>A (p.Gly117Ser)

gnomAD frequency: 0.00001  dbSNP: rs770944877
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000671967 SCV000797014 likely pathogenic Citrullinemia type I 2018-01-09 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001376559 SCV001217718 pathogenic Citrullinemia 2023-11-02 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 117 of the ASS1 protein (p.Gly117Ser). This variant is present in population databases (rs770944877, gnomAD 0.003%). This missense change has been observed in individual(s) with citrullinemia type I (PMID: 12815590, 16124451, 27287393). ClinVar contains an entry for this variant (Variation ID: 556029). 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 ASS1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ASS1 function (PMID: 27287393). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000671967 SCV002019978 pathogenic Citrullinemia type I 2021-03-02 criteria provided, single submitter clinical testing
Genetics and Molecular Pathology, SA Pathology RCV000671967 SCV002761925 pathogenic Citrullinemia type I 2020-02-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001376559 SCV004030158 pathogenic Citrullinemia 2023-07-27 criteria provided, single submitter clinical testing Variant summary: ASS1 c.349G>A (p.Gly117Ser) results in a non-conservative amino acid change in 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 1.2e-05 in 247280 control chromosomes. c.349G>A has been reported in the literature in multiple individuals affected with Citrullinemia Type I, including in homozygotes with neonatal/infantile onset (e.g. Diez-Fernandez_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a complete loss of normal argininosuccinate synthetase enzyme activity (e.g. Diez-Fernandez_2016). The following publication has been ascertained in the context of this evaluation (PMID: 27287393). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=4) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000671967 SCV004205007 pathogenic Citrullinemia type I 2024-03-04 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000671967 SCV005679644 pathogenic Citrullinemia type I 2024-01-24 criteria provided, single submitter clinical testing
Natera, Inc. RCV000671967 SCV001453080 pathogenic Citrullinemia type I 2020-09-16 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004756006 SCV005362668 pathogenic ASS1-related disorder 2024-07-10 no assertion criteria provided clinical testing The ASS1 c.349G>A variant is predicted to result in the amino acid substitution p.Gly117Ser. This variant has been reported in the homozygous state in several patients with a biochemical diagnosis of citrullinemia (Gao et al. 2003. PubMed ID: 12815590; Wasant et al. 2005. PubMed ID: 16124451; Diez-Fernandez et al. 2016. PubMed ID: 27287393). The p.Gly117Ser change was reported to decrease ASS1 enzyme activity to <2% of wild-type (Diez-Fernandez et al. 2016. PubMed ID: 27287393). This variant is reported in 0.0027% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.

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