ClinVar Miner

Submissions for variant NM_001673.5(ASNS):c.146G>A (p.Arg49Gln) (rs769236847)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000432896 SCV000524216 likely pathogenic not provided 2016-02-25 criteria provided, single submitter clinical testing The R49Q variant in the ASNS gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R49Q variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R49Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. The R49Q variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000714524 SCV000845219 likely pathogenic Asparagine synthetase deficiency 2019-01-01 criteria provided, single submitter clinical testing
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000714524 SCV000891623 uncertain significance Asparagine synthetase deficiency 2017-12-30 criteria provided, single submitter curation
Laboratoire de Génétique Moléculaire, CHU Bordeaux RCV000432896 SCV001468998 pathogenic not provided criteria provided, single submitter clinical testing
Invitae RCV000432896 SCV001587973 pathogenic not provided 2020-09-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 49 of the ASNS protein (p.Arg49Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs769236847, ExAC 0.001%). This variant has been observed in individual(s) with asparagine synthetase deficiency (PMID: 29279279, 30978478). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 383733). 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 ASNS protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000714524 SCV001446397 pathogenic Asparagine synthetase deficiency 2020-05-26 no assertion criteria provided literature only
Natera, Inc. RCV000714524 SCV001453755 likely pathogenic Asparagine synthetase deficiency 2020-09-16 no assertion criteria provided clinical testing

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