VCV000091841.12 - ClinVar

NM_001673.5(ASNS):c.1648C>T (p.Arg550Cys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

This variant is part of a Genotype

NM_133436.3(ASNS):c.[1439C>T];[1648C>T]

Identifiers

NM_001673.5(ASNS):c.1648C>T (p.Arg550Cys)

Variation ID: 91841 Accession: VCV000091841.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q21.3 7: 97852297 (GRCh38) [ NCBI UCSC ] 7: 97481609 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 8, 2015	Feb 14, 2024	Nov 6, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001673.5:c.1648C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001664.3:p.Arg550Cys	missense
NM_001178075.2:c.1585C>T	NP_001171546.1:p.Arg529Cys	missense
NM_001178076.2:c.1399C>T	NP_001171547.1:p.Arg467Cys	missense
NM_001178077.1:c.1399C>T	NP_001171548.1:p.Arg467Cys	missense
NM_001352496.2:c.1648C>T	NP_001339425.1:p.Arg550Cys	missense
NM_133436.3:c.1648C>T	NP_597680.2:p.Arg550Cys	missense
NM_183356.4:c.1648C>T	NP_899199.2:p.Arg550Cys	missense
NR_147989.1:n.3351C>T		non-coding transcript variant
NC_000007.14:g.97852297G>A
NC_000007.13:g.97481609G>A
NG_033870.2:g.81266C>T
	P08243:p.Arg550Cys

... more HGVS ... less HGVS

Protein change

R550C, R529C, R467C

Other names

Canonical SPDI

NC_000007.14:97852296:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

Links

ClinGen: CA331775 UniProtKB: P08243#VAR_070898 OMIM: 108370.0002 dbSNP: rs398122974 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ASNS		-	-	GRCh38 GRCh37	6	740
CZ1P-ASNS	-	-	-	GRCh38	-	720

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Feb 3, 2022	RCV000077749.7
not provided	Pathogenic (1)	criteria provided, single submitter	Nov 6, 2023	RCV001064729.8

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Feb 03, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002104071.1 First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022	Publications: PubMed (3) PubMed: 27522229‚ 25758715‚ 24139043 Comment: Variant summary: ASNS c.1648C>T (p.Arg550Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more) Variant summary: ASNS c.1648C>T (p.Arg550Cys) 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 1.6e-05 in 251360 control chromosomes (gnomAD). c.1648C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Asparagine Synthetase Deficiency and was shown to segregate with disease in families (e.g. Ruzzo_2013, Mercimek-Mahmutoglu_2015, Gataullina_2016). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Likely pathogenic (Oct 18, 2016)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: clinical testing	Congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000486994.2 First in ClinVar: Oct 11, 2015 Last updated: Dec 24, 2022	Publications: PubMed (3) PubMed: 24139043‚ 25758715‚ 27522229
Pathogenic (Nov 06, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001229647.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 24139043‚ 27522229 Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 550 of the ASNS protein … (more) This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 550 of the ASNS protein (p.Arg550Cys). This variant is present in population databases (rs398122974, gnomAD 0.007%). This missense change has been observed in individual(s) with asparagine synthetase deficiency (PMID: 24139043, 27522229). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 91841). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Oct 16, 2013)	no assertion criteria provided Method: literature only	ASPARAGINE SYNTHETASE DEFICIENCY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000109555.3 First in ClinVar: Dec 26, 2013 Last updated: May 30, 2018	Publications: PubMed (1) PubMed: 24139043 Comment on evidence: In 3 male sibs, born of consanguineous Bangladeshi parents, with asparagine synthetase deficiency (ASNSD; 615574), Ruzzo et al. (2013) identified a homozygous c.1648C-T transition in … (more) In 3 male sibs, born of consanguineous Bangladeshi parents, with asparagine synthetase deficiency (ASNSD; 615574), Ruzzo et al. (2013) identified a homozygous c.1648C-T transition in the ASNS gene, resulting in an arg550-to-cys (R550C) substitution. Three male sibs from a French Canadian family with the disorder were found to be compound heterozygous for R550C and a c.17C-A transversion, resulting in an ala6-to-glu (A6E; 108370.0003) substitution. Both mutations occurred at highly conserved residues. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Neither mutation was found in the dbSNP (build 135), 1000 Genomes Project, or Exome Sequencing Project databases or in 1,160 controls, 169 in-house exomes, or 300 ancestry-matched controls. In vitro functional expression studies in HEK293 and COS-7 cells showed decreased amounts of mutant A6E protein compared to wildtype, whereas the mutant R550C protein was increased compared to wildtype. Asparagine levels were decreased in 1 patient from each family. Ruzzo et al. (2013) postulated a loss-of-function effect, either by decreased amounts of ASNS protein (A6E) or decreased function (R550C). (less)

Comment:

Variant summary: ASNS c.1648C>T (p.Arg550Cys) 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 1.6e-05 in 251360 control chromosomes (gnomAD). c.1648C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Asparagine Synthetase Deficiency and was shown to segregate with disease in families (e.g. Ruzzo_2013, Mercimek-Mahmutoglu_2015, Gataullina_2016). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 550 of the ASNS protein (p.Arg550Cys). This variant is present in population databases (rs398122974, gnomAD 0.007%). This missense change has been observed in individual(s) with asparagine synthetase deficiency (PMID: 24139043, 27522229). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 91841). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Epileptic Phenotype of Two Siblings with Asparagine Synthesis Deficiency Mimics Neonatal Pyridoxine-Dependent Epilepsy.	Gataullina S	Neuropediatrics	2016	PMID: 27522229
Prevalence of inherited neurotransmitter disorders in patients with movement disorders and epilepsy: a retrospective cohort study.	Mercimek-Mahmutoglu S	Orphanet journal of rare diseases	2015	PMID: 25758715
Deficiency of asparagine synthetase causes congenital microcephaly and a progressive form of encephalopathy.	Ruzzo EK	Neuron	2013	PMID: 24139043

Text-mined citations for rs398122974 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001673.5(ASNS):c.1648C>T (p.Arg550Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs398122974 ...