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

gnomAD frequency: 0.00004  dbSNP: rs769236847

Total submissions: 8

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	Congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome	2019-01-01	criteria provided, single submitter	clinical testing
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	RCV000714524	SCV000891623	likely pathogenic	Congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome	2023-12-30	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	2023-10-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 49 of the ASNS protein (p.Arg49Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with asparagine synthetase deficiency (PMID: 29279279, 30978478, 33287870). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ASNS protein function. For these reasons, this variant has been classified as Pathogenic.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV002274029	SCV002558923	pathogenic	Neurodevelopmental delay		criteria provided, single submitter	clinical testing
OMIM	RCV000714524	SCV001446397	pathogenic	Congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome	2020-05-26	no assertion criteria provided	literature only
Natera, Inc.	RCV000714524	SCV001453755	likely pathogenic	Congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome	2020-09-16	no assertion criteria provided	clinical testing