VCV000002402.33 - ClinVar

NM_000048.4(ASL):c.532G>A (p.Val178Met)

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.

(15)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000048.4(ASL):c.532G>A (p.Val178Met)

Variation ID: 2402 Accession: VCV000002402.33

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q11.21 7: 66086751 (GRCh38) [ NCBI UCSC ] 7: 65551738 (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	Jul 18, 2015	Aug 25, 2024	Mar 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000048.4:c.532G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000039.2:p.Val178Met	missense
NM_001024943.2:c.532G>A	NP_001020114.1:p.Val178Met	missense
NM_001024944.2:c.532G>A	NP_001020115.1:p.Val178Met	missense
NM_001024946.2:c.524+89G>A		intron variant
NC_000007.14:g.66086751G>A
NC_000007.13:g.65551738G>A
NG_009288.1:g.15963G>A
	P04424:p.Val178Met

... more HGVS ... less HGVS

Protein change

V178M

Other names

Canonical SPDI

NC_000007.14:66086750: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.

0.00020 (A)

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

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

The Genome Aggregation Database (gnomAD), exomes 0.00029

The Genome Aggregation Database (gnomAD) 0.00034

Trans-Omics for Precision Medicine (TOPMed) 0.00035

Exome Aggregation Consortium (ExAC) 0.00051

Links

ClinGen: CA252264 UniProtKB: P04424#VAR_017572 OMIM: 608310.0005 dbSNP: rs28941473 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.
ASL		-	-	GRCh38 GRCh37	859	895

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.
Argininosuccinate lyase deficiency	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Mar 30, 2024	RCV000002503.23
not provided	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	Feb 12, 2023	RCV000723377.16

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 (Jan 06, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Argininosuccinate lyase deficiency Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000694152.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017	Publications: PubMed (3) PubMed: 12408190‚ 21667091‚ 12384776 Comment: Variant summary: The ASL c.532G>A (p.Val178Met) variant located in the central core heliz bundle forming the tetramer (per Balmer_2012 PMID: 24166829) causes a missense change … (more) Variant summary: The ASL c.532G>A (p.Val178Met) variant located in the central core heliz bundle forming the tetramer (per Balmer_2012 PMID: 24166829) causes a missense change involving a conserved nucleotide, which 3/5 in silico tools predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 35/68898 (1/1968), which does not exceed the estimated maximal expected allele frequency for a pathogenic ASL variant of 1/236. Multiple publications have reported the variant in affected individuals, who were homozygous or compound heterozygous. Functional studyies showed variant with ASL activity about 5% of WT's . In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
Pathogenic (Dec 26, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Argininosuccinate lyase deficiency Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001194003.1 First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020	Publications: PubMed (3) PubMed: 12408190‚ 21667091‚ 24166829 Comment: NM_001024943.1(ASL):c.532G>A(V178M) is classified as pathogenic in the context of argininosuccinic aciduria. Sources cited for classification include the following: PMID 12408190, 21667091, 21667091 and 24166829. Classification … (more) NM_001024943.1(ASL):c.532G>A(V178M) is classified as pathogenic in the context of argininosuccinic aciduria. Sources cited for classification include the following: PMID 12408190, 21667091, 21667091 and 24166829. Classification of NM_001024943.1(ASL):c.532G>A(V178M) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
Pathogenic (Jan 11, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV002525761.1 First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022	Publications: PubMed (12) PubMed: 12384776‚ 12408190‚ 17326097‚ 19703900‚ 20236848‚ 21667091‚ 22231378‚ 24166829‚ 25778938‚ 31589614‚ 31943503‚ 31980526 Comment: PP4, PM2, PM3, PS3, PS4
Pathogenic (May 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Argininosuccinate lyase deficiency Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002800941.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Feb 12, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000238691.3 First in ClinVar: Jul 18, 2015 Last updated: Feb 18, 2023	Comment: Published functional studies found this variant is associated with significantly reduced argininosuccinate lyase activity compared to wild-type (Engel et al., 2012; Doimo et al., 2012; … (more) Published functional studies found this variant is associated with significantly reduced argininosuccinate lyase activity compared to wild-type (Engel et al., 2012; Doimo et al., 2012; Hu et al., 2015); This variant is associated with the following publications: (PMID: 28251416, 24166829, 17326097, 20236848, 34598035, 31589614, 22231378, 12384776, 19703900, 25778938, 31943503, 12408190, 31980526, 21667091) (less)
Pathogenic (Jul 13, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005199587.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Mar 24, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000232467.5 First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018	Publications: PubMed (2) PubMed: 12408190‚ 22231378 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ASL Number of individuals with the variant: 3 Sex: mixed
Pathogenic (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Argininosuccinate lyase deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000631870.7 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (6) PubMed: 12408190‚ 17326097‚ 19703900‚ 20236848‚ 21667091‚ 25778938 Comment: This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 178 of the ASL protein (p.Val178Met). … (more) This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 178 of the ASL protein (p.Val178Met). This variant is present in population databases (rs28941473, gnomAD 0.07%). This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 12408190, 17326097, 19703900, 20236848). ClinVar contains an entry for this variant (Variation ID: 2402). 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 ASL protein function. Experimental studies have shown that this missense change affects ASL function (PMID: 19703900, 21667091, 25778938). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Argininosuccinate lyase deficiency Affected status: no Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV005052007.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Pathogenic (Mar 30, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Argininosuccinate lyase deficiency Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004040733.2 First in ClinVar: Oct 07, 2023 Last updated: Jun 17, 2024
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001918675.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Pathogenic (Sep 01, 2002)	no assertion criteria provided Method: literature only	ARGININOSUCCINIC ACIDURIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000022661.3 First in ClinVar: Apr 04, 2013 Last updated: Nov 29, 2021	Publications: Kleijer, W. J., Garritsen, V. H., (more...) Kleijer, W. J., Garritsen, V. H., Linnebank, M., Mooyer, P., Huijmans, J. G. M., Mustonen, A., Simola, K. O. J., Arslan-Kirchner, M., Battini, R., Briones, P., Cardo, E., Mandel, H., Tschiedel, E., Wanders, R. J. A., Koch, H. G. Clinical, enzymatic, and molecular genetic characterization of a biochemical variant type of argininosuccinic aciduria: prenatal and postnatal diagnosis in 5 unrelated families. J. Inherit. Metab. Dis. 25: 399-410, 2002. Comment on evidence: In a patient from a family with variable age of onset of ASL deficiency (207900) and considerable residual ASL activity, Kleijer et al. (2002) identified … (more) In a patient from a family with variable age of onset of ASL deficiency (207900) and considerable residual ASL activity, Kleijer et al. (2002) identified a homozygous 532G-A transition in the ASL gene, resulting in a val178-to-met (V178M) substitution. (less)
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Argininosuccinate lyase deficiency Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001459674.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001739938.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001954513.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
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Citation text

Kleijer, W. J., Garritsen, V. H., Linnebank, M., Mooyer, P., Huijmans, J. G. M., Mustonen, A., Simola, K. O. J., Arslan-Kirchner, M., Battini, R., Briones, P., Cardo, E., Mandel, H., Tschiedel, E., Wanders, R. J. A., Koch, H. G. Clinical, enzymatic, and molecular genetic characterization of a biochemical variant type of argininosuccinic aciduria: prenatal and postnatal diagnosis in 5 unrelated families. J. Inherit. Metab. Dis. 25: 399-410, 2002.

Comment:

Variant summary: The ASL c.532G>A (p.Val178Met) variant located in the central core heliz bundle forming the tetramer (per Balmer_2012 PMID: 24166829) causes a missense change involving a conserved nucleotide, which 3/5 in silico tools predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 35/68898 (1/1968), which does not exceed the estimated maximal expected allele frequency for a pathogenic ASL variant of 1/236. Multiple publications have reported the variant in affected individuals, who were homozygous or compound heterozygous. Functional studyies showed variant with ASL activity about 5% of WT's . In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Comment:

NM_001024943.1(ASL):c.532G>A(V178M) is classified as pathogenic in the context of argininosuccinic aciduria. Sources cited for classification include the following: PMID 12408190, 21667091, 21667091 and 24166829. Classification of NM_001024943.1(ASL):c.532G>A(V178M) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Comment:

Published functional studies found this variant is associated with significantly reduced argininosuccinate lyase activity compared to wild-type (Engel et al., 2012; Doimo et al., 2012; Hu et al., 2015); This variant is associated with the following publications: (PMID: 28251416, 24166829, 17326097, 20236848, 34598035, 31589614, 22231378, 12384776, 19703900, 25778938, 31943503, 12408190, 31980526, 21667091)

Comment:

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 178 of the ASL protein (p.Val178Met). This variant is present in population databases (rs28941473, gnomAD 0.07%). This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 12408190, 17326097, 19703900, 20236848). ClinVar contains an entry for this variant (Variation ID: 2402). 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 ASL protein function. Experimental studies have shown that this missense change affects ASL function (PMID: 19703900, 21667091, 25778938). 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
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging.	Hou YC	Proceedings of the National Academy of Sciences of the United States of America	2020	PMID: 31980526
From genotype to phenotype: Early prediction of disease severity in argininosuccinic aciduria.	Zielonka M	Human mutation	2020	PMID: 31943503
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes.	Capalbo A	PLoS genetics	2019	PMID: 31589614
Unstable argininosuccinate lyase in variant forms of the urea cycle disorder argininosuccinic aciduria.	Hu L	Journal of inherited metabolic disease	2015	PMID: 25778938
Mutations and polymorphisms in the human argininosuccinate lyase (ASL) gene.	Balmer C	Human mutation	2014	PMID: 24166829
Yeast complementation is sufficiently sensitive to detect the residual activity of ASL alleles associated with mild forms of argininosuccinic aciduria.	Doimo M	Journal of inherited metabolic disease	2012	PMID: 22231378
Bacterial expression of mutant argininosuccinate lyase reveals imperfect correlation of in-vitro enzyme activity with clinical phenotype in argininosuccinic aciduria.	Engel K	Journal of inherited metabolic disease	2012	PMID: 21667091
Long-term outcome of patients with argininosuccinate lyase deficiency diagnosed by newborn screening in Austria.	Mercimek-Mahmutoglu S	Molecular genetics and metabolism	2010	PMID: 20236848
Functional complementation in yeast allows molecular characterization of missense argininosuccinate lyase mutations.	Trevisson E	The Journal of biological chemistry	2009	PMID: 19703900
Argininosuccinate lyase deficiency: mutational spectrum in Italian patients and identification of a novel ASL pseudogene.	Trevisson E	Human mutation	2007	PMID: 17326097
Clinical, enzymatic, and molecular genetic characterization of a biochemical variant type of argininosuccinic aciduria: prenatal and postnatal diagnosis in five unrelated families.	Kleijer WJ	Journal of inherited metabolic disease	2002	PMID: 12408190
Argininosuccinate lyase (ASL) deficiency: mutation analysis in 27 patients and a completed structure of the human ASL gene.	Linnebank M	Human genetics	2002	PMID: 12384776
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ASL	-	-	-	-
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Text-mined citations for rs28941473 ...

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_000048.4(ASL):c.532G>A (p.Val178Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs28941473 ...