VCV000092361.28 - ClinVar

NM_000048.4(ASL):c.446+1G>A

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.446+1G>A

Variation ID: 92361 Accession: VCV000092361.28

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q11.21 7: 66083175 (GRCh38) [ NCBI UCSC ] 7: 65548162 (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	Dec 6, 2016	Jun 17, 2024	Mar 12, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000048.4:c.446+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001024943.2:c.446+1G>A		splice donor
NM_001024944.2:c.446+1G>A		splice donor
NM_001024946.2:c.446+1G>A		splice donor
NC_000007.14:g.66083175G>A
NC_000007.13:g.65548162G>A
NG_009288.1:g.12387G>A

... more HGVS ... less HGVS

Protein change

Other names

IVS5DS, G-A, +1

Canonical SPDI

NC_000007.14:66083174: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), exomes 0.00004

Exome Aggregation Consortium (ExAC) 0.00005

Trans-Omics for Precision Medicine (TOPMed) 0.00005

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

The Genome Aggregation Database (gnomAD) 0.00008

Links

ClinGen: CA285298 OMIM: 608310.0003 dbSNP: rs142637046 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.
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Feb 8, 2021	RCV000078011.14
Argininosuccinate lyase deficiency	Pathogenic (10)	criteria provided, multiple submitters, no conflicts	Mar 12, 2024	RCV000409952.24

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 (Mar 12, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Argininosuccinate lyase deficiency Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004041540.3 First in ClinVar: Oct 07, 2023 Last updated: Jun 17, 2024
Pathogenic (Jun 05, 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: SCV000694151.1 First in ClinVar: Jan 06, 2017 Last updated: Jan 06, 2017	Publications: PubMed (1) PubMed: 12384776 Comment: Variant summary: The ASL c.446+1G>A variant involves the alteration of a conserved intronic nucleotide that 5/5 splice prediction tools predict a significant impact on splicing, … (more) Variant summary: The ASL c.446+1G>A variant involves the alteration of a conserved intronic nucleotide that 5/5 splice prediction tools predict a significant impact on splicing, which is supported by a functional study, Linnebank_2002. This variant was found in 6/117678 control chromosomes at a frequency of 0.000051, which does not exceed the estimated maximal expected allele frequency of a pathogenic ASL variant (0.0042258). The variant of interest (legacy name IVS5+1G>A) has been reported in multiple affected individuals as both compound heterozygotes and homozygotes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
Pathogenic (Jul 28, 2017)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Argininosuccinate lyase deficiency Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV000743790.1 First in ClinVar: Jan 06, 2017 Last updated: Jan 06, 2017
Pathogenic (Feb 08, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000238711.7 First in ClinVar: Jul 18, 2015 Last updated: Dec 06, 2016	Comment: Canonical splice site variant predicted to result in a null allele and deletion of the upstream exon in a gene for which loss-of-function is a … (more) Canonical splice site variant predicted to result in a null allele and deletion of the upstream exon in a gene for which loss-of-function is a known mechanism of disease (Linnebank et al., 2002); Identified in a patient with late onset argininosuccinic aciduria who also harbored a second ASL variant (Baruteau et al., 2017); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25087612, 25525159, 24166829, 12384776, 28251416, 31589614) (less)
Pathogenic (May 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Argininosuccinate lyase deficiency Affected status: yes Allele origin: germline	3billion Accession: SCV002521250.1 First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022	Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Canonical splice site: predicted to alter splicing … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000092361). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Elevated plasma citrulline (present) , Hyperammonemia (present) , Vomiting (present) , Feeding difficulties (present) , Generalized hypotonia (present)
Pathogenic (Mar 10, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Argininosuccinate lyase deficiency Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581403.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PM3_STR, PS4_MOD, PM2_SUP	Number of individuals with the variant: 1 Sex: male
Pathogenic (Aug 24, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	Argininosuccinate lyase deficiency Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV004563727.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Comment: The ASL c.446+1G>A variant (rs142637046) is reported in the literature in many individuals with argininosuccinic aciduria (Linnebank 2002, Toquet 2021). This variant is reported in … (more) The ASL c.446+1G>A variant (rs142637046) is reported in the literature in many individuals with argininosuccinic aciduria (Linnebank 2002, Toquet 2021). This variant is reported in ClinVar (Variation ID: 92361) and is found in the general population with an overall allele frequency of 0.005% (13/280,896 alleles) in the Genome Aggregation Database (v2.1.1). This variant disrupts the canonical splice donor site of intron 6, and experimental evidence found this variant results in the skipping of exon 5 (Linnebank 2002). Based on available information, this variant is considered to be pathogenic. References: Linnebank M et al. Argininosuccinate lyase (ASL) deficiency: mutation analysis in 27 patients and a completed structure of the human ASL gene. Hum Genet. 2002 Oct;111(4-5):350-9. PMID: 12384776. Toquet S et al. Adult-onset diagnosis of urea cycle disorders: Results of a French cohort of 71 patients. J Inherit Metab Dis. 2021 Sep;44(5):1199-1214. PMID: 34014557. (less)
Pathogenic (Aug 22, 2013)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000109849.8 First in ClinVar: Jan 17, 2014 Last updated: Dec 06, 2016	Publications: PubMed (1) PubMed: 12384776 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: 2 Sex: mixed
Pathogenic (Nov 10, 2021)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021)) Method: clinical testing	Argininosuccinate lyase deficiency Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV002060370.2 First in ClinVar: Jan 15, 2022 Last updated: Nov 29, 2022	Publications: PubMed (1) PubMed: 12384776 Comment: NM_001024943.1(ASL):c.446+1G>A is a canonical splice variant classified as pathogenic in the context of argininosuccinic aciduria. c.446+1G>A has been observed in cases with relevant disease (PMID: … (more) NM_001024943.1(ASL):c.446+1G>A is a canonical splice variant classified as pathogenic in the context of argininosuccinic aciduria. c.446+1G>A has been observed in cases with relevant disease (PMID: 12384776). Functional assessments of this variant are available in the literature (PMID: 12384776). c.446+1G>A has been observed in population frequency databases (gnomAD: NFE <0.001%). In summary, NM_001024943.1(ASL):c.446+1G>A is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
Pathogenic (Jan 18, 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: SCV000822831.7 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 28492532‚ 16199547‚ 2263616‚ 24166829‚ 12384776 Comment: This sequence change affects a donor splice site in intron 6 of the ASL gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more) This sequence change affects a donor splice site in intron 6 of the ASL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ASL are known to be pathogenic (PMID: 2263616, 24166829). This variant is present in population databases (rs142637046, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with argininosuccinate lyase (ASL) deficiency (PMID: 12384776). This variant is also known as IVS5+1G>A. ClinVar contains an entry for this variant (Variation ID: 92361). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Oct 01, 2002)	no assertion criteria provided Method: literature only	ARGININOSUCCINIC ACIDURIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000022659.2 First in ClinVar: Apr 04, 2013 Last updated: Jun 03, 2017	Publications: PubMed (1) PubMed: 12384776 Comment on evidence: Linnebank et al. (2002) found that 15 of 54 ASL deficiency (207900)-related alleles had an IVS5+1G-A splice site mutation in the ASL gene that resulted … (more) Linnebank et al. (2002) found that 15 of 54 ASL deficiency (207900)-related alleles had an IVS5+1G-A splice site mutation in the ASL gene that resulted in the deletion of 21 amino acids. (less)
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Argininosuccinate lyase deficiency Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001459672.1 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	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001920381.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001975953.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
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: SCV001951975.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
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Comment:

Variant summary: The ASL c.446+1G>A variant involves the alteration of a conserved intronic nucleotide that 5/5 splice prediction tools predict a significant impact on splicing, which is supported by a functional study, Linnebank_2002. This variant was found in 6/117678 control chromosomes at a frequency of 0.000051, which does not exceed the estimated maximal expected allele frequency of a pathogenic ASL variant (0.0042258). The variant of interest (legacy name IVS5+1G>A) has been reported in multiple affected individuals as both compound heterozygotes and homozygotes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Comment:

Canonical splice site variant predicted to result in a null allele and deletion of the upstream exon in a gene for which loss-of-function is a known mechanism of disease (Linnebank et al., 2002); Identified in a patient with late onset argininosuccinic aciduria who also harbored a second ASL variant (Baruteau et al., 2017); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25087612, 25525159, 24166829, 12384776, 28251416, 31589614)

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000092361). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

The ASL c.446+1G>A variant (rs142637046) is reported in the literature in many individuals with argininosuccinic aciduria (Linnebank 2002, Toquet 2021). This variant is reported in ClinVar (Variation ID: 92361) and is found in the general population with an overall allele frequency of 0.005% (13/280,896 alleles) in the Genome Aggregation Database (v2.1.1). This variant disrupts the canonical splice donor site of intron 6, and experimental evidence found this variant results in the skipping of exon 5 (Linnebank 2002). Based on available information, this variant is considered to be pathogenic. References: Linnebank M et al. Argininosuccinate lyase (ASL) deficiency: mutation analysis in 27 patients and a completed structure of the human ASL gene. Hum Genet. 2002 Oct;111(4-5):350-9. PMID: 12384776. Toquet S et al. Adult-onset diagnosis of urea cycle disorders: Results of a French cohort of 71 patients. J Inherit Metab Dis. 2021 Sep;44(5):1199-1214. PMID: 34014557.

Comment:

NM_001024943.1(ASL):c.446+1G>A is a canonical splice variant classified as pathogenic in the context of argininosuccinic aciduria. c.446+1G>A has been observed in cases with relevant disease (PMID: 12384776). Functional assessments of this variant are available in the literature (PMID: 12384776). c.446+1G>A has been observed in population frequency databases (gnomAD: NFE <0.001%). In summary, NM_001024943.1(ASL):c.446+1G>A is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Comment:

This sequence change affects a donor splice site in intron 6 of the ASL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ASL are known to be pathogenic (PMID: 2263616, 24166829). This variant is present in population databases (rs142637046, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with argininosuccinate lyase (ASL) deficiency (PMID: 12384776). This variant is also known as IVS5+1G>A. ClinVar contains an entry for this variant (Variation ID: 92361). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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
Mutations and polymorphisms in the human argininosuccinate lyase (ASL) gene.	Balmer C	Human mutation	2014	PMID: 24166829
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547
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
Molecular analysis of human argininosuccinate lyase: mutant characterization and alternative splicing of the coding region.	Walker DC	Proceedings of the National Academy of Sciences of the United States of America	1990	PMID: 2263616
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ASL	-	-	-	-

Text-mined citations for rs142637046 ...

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.446+1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs142637046 ...