Submissions for variant NM_001673.5(ASNS):c.1084T>G (p.Phe362Val)

dbSNP: rs398122973

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000812578	SCV000952896	pathogenic	not provided	2023-10-15	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 362 of the ASNS protein (p.Phe362Val). This variant is present in population databases (rs398122973, gnomAD 0.0009%). This missense change has been observed in individuals with asparagine synthetase deficiency (PMID: 24139043). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 91840). 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. Experimental studies have shown that this missense change affects ASNS function (PMID: 24139043). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000812578	SCV001155160	likely pathogenic	not provided	2018-12-01	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000077748	SCV002507038	likely pathogenic	Congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome	2022-05-04	criteria provided, single submitter	curation	The homozygous p.Phe362Val variant in ASNS was identified by our study in 1 individual with asparagine synthetase deficiency. The variant has been reported in 4 Iranian Jewish individuals with asparagine synthetase deficiency (PMID: 24139043), segregated with disease in 2 affected relatives from 2 families (PMID: 24139043), but was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 91840) as pathogenic by Invitae and OMIM, and as likely pathogenic by CeGaT Praxis fuer Humangenetik Tuebingen. In vitro functional studies provide some evidence that the p.Phe362Val variant may impact protein function (PMID: 24139043). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in 5 affected homozygotes, and in 5 individuals with asparagine synthetase deficiency increases the likelihood that the p.Phe362Val variant is pathogenic (PMID: 24139043). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3, PP1_moderate, PS3_moderate (Richards 2015).
Fulgent Genetics, Fulgent Genetics	RCV000077748	SCV002794843	likely pathogenic	Congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome	2022-03-18	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000077748	SCV003817918	pathogenic	Congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome	2022-06-17	criteria provided, single submitter	clinical testing
OMIM	RCV000077748	SCV000109554	pathogenic	Congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome	2013-10-16	no assertion criteria provided	literature only
Natera, Inc.	RCV000077748	SCV001453754	pathogenic	Congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome	2020-09-16	no assertion criteria provided	clinical testing