VCV000203615.21 - ClinVar

NM_000048.4(ASL):c.649C>T (p.Arg217Ter)

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.

(8)

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.649C>T (p.Arg217Ter)

Variation ID: 203615 Accession: VCV000203615.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q11.21 7: 66087380 (GRCh38) [ NCBI UCSC ] 7: 65552367 (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	Aug 25, 2024	Feb 19, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000048.4:c.649C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000039.2:p.Arg217Ter	nonsense
NM_001024943.2:c.649C>T	NP_001020114.1:p.Arg217Ter	nonsense
NM_001024944.2:c.649C>T	NP_001020115.1:p.Arg217Ter	nonsense
NM_001024946.2:c.571C>T	NP_001020117.1:p.Arg191Ter	nonsense
NC_000007.14:g.66087380C>T
NC_000007.13:g.65552367C>T
NG_009288.1:g.16592C>T

... more HGVS ... less HGVS

Protein change

R217*, R191*

Other names

p.R217*:CGA>TGA

Canonical SPDI

NC_000007.14:66087379:C:T

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.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00003

The Genome Aggregation Database (gnomAD) 0.00004

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA312325 dbSNP: rs369879957 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 (2)	criteria provided, multiple submitters, no conflicts	Aug 11, 2023	RCV000185765.8
Argininosuccinate lyase deficiency	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Feb 19, 2024	RCV000668606.17

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 (Aug 07, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Argininosuccinate lyase deficiency Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000793237.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (1) PubMed: 24166829
Pathogenic (Oct 18, 2021)	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: SCV001363606.2 First in ClinVar: Jun 22, 2020 Last updated: Nov 20, 2021	Publications: PubMed (3) PubMed: 24166829‚ 30285816‚ 31990680 Comment: Variant summary: ASL c.649C>T (p.Arg217X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: ASL c.649C>T (p.Arg217X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 245080 control chromosomes. c.649C>T has been reported in the literature in multiple individuals affected with Argininosuccinic Aciduria (in compound heterozygous or homozygous state (Balmer_2014, Bijarnia-Mahay_2018, Burrage_2020). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (May 28, 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: SCV000894436.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Aug 11, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000238694.13 First in ClinVar: Jul 18, 2015 Last updated: Aug 18, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene … (more) Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31943503, 30285816, 24166829, 25087612, 31990680) (less)
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: SCV001206851.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024	Publications: PubMed (3) PubMed: 2263616‚ 24166829‚ 30285816 Comment: This sequence change creates a premature translational stop signal (p.Arg217) in the ASL gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg217) in the ASL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ASL are known to be pathogenic (PMID: 2263616, 24166829). 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 premature translational stop signal has been observed in individual(s) with clinical features of a urea cycle disorder (PMID: 30285816). ClinVar contains an entry for this variant (Variation ID: 203615). 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 (Feb 19, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Argininosuccinate lyase deficiency Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004202972.3 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
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: SCV005199588.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (May 04, 2021)	no assertion criteria provided Method: clinical testing	Argininosuccinate lyase deficiency Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002076025.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022

Comment:

Variant summary: ASL c.649C>T (p.Arg217X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 245080 control chromosomes. c.649C>T has been reported in the literature in multiple individuals affected with Argininosuccinic Aciduria (in compound heterozygous or homozygous state (Balmer_2014, Bijarnia-Mahay_2018, Burrage_2020). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31943503, 30285816, 24166829, 25087612, 31990680)

Comment:

This sequence change creates a premature translational stop signal (p.Arg217*) in the ASL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ASL are known to be pathogenic (PMID: 2263616, 24166829). 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 premature translational stop signal has been observed in individual(s) with clinical features of a urea cycle disorder (PMID: 30285816). ClinVar contains an entry for this variant (Variation ID: 203615). 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
Chronic liver disease and impaired hepatic glycogen metabolism in argininosuccinate lyase deficiency.	Burrage LC	JCI insight	2020	PMID: 31990680
Urea cycle disorders in India: clinical course, biochemical and genetic investigations, and prenatal testing.	Bijarnia-Mahay S	Orphanet journal of rare diseases	2018	PMID: 30285816
Mutations and polymorphisms in the human argininosuccinate lyase (ASL) gene.	Balmer C	Human mutation	2014	PMID: 24166829
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

Text-mined citations for rs369879957 ...

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.649C>T (p.Arg217Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs369879957 ...