Variant summary: The c.299T>C (p.Ile100Thr) in ASL gene is a missense change that alters a highly conserved nucleotide and 4/5 in silico tools predict deleterious outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.00014 (17/118940 chrs tested). This frequency does not exceed the maximal expected allele frequency for a pathogenic variant in ASL gene (0.004). The results of functional studies are contradictious, depending on the expression system and ranging from ~90% of residual enzymatic activity in HEK293T to no detectable activity in bacterial cells. Since there is no information from the most reliable functional assay, such as citrulline incorporation was published at the time of evaluation, the results from the other functional assays mentioned above should be taken with caution. The variant was found homozygously or in compound heterozygosity in multiple affected individuals with established diagnosis of ASLD. Taken together, the variant was classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000048.4(ASL):c.299T>C (p.Ile100Thr)
Germline
Classification
Help
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.
(6)
Help
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
6
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.299T>C (p.Ile100Thr)
Variation ID: 495379 Accession: VCV000495379.14
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q11.21 7: 66082887 (GRCh38) [ NCBI UCSC ] 7: 65547874 (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 Mar 17, 2018 Jul 23, 2024 Jun 5, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000048.4:c.299T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000039.2:p.Ile100Thr missense NM_001024943.2:c.299T>C NP_001020114.1:p.Ile100Thr missense NM_001024944.2:c.299T>C NP_001020115.1:p.Ile100Thr missense NM_001024946.2:c.299T>C NP_001020117.1:p.Ile100Thr missense NC_000007.14:g.66082887T>C NC_000007.13:g.65547874T>C NG_009288.1:g.12099T>C - Protein change
- I100T
- Other names
- -
- Canonical SPDI
- NC_000007.14:66082886:T:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00003
1000 Genomes Project 30x 0.00016
The Genome Aggregation Database (gnomAD) 0.00022
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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 |
858 | 894 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Mar 17, 2024 | RCV000587929.11 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jun 5, 2024 | RCV001576060.4 |
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
(Sep 09, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Argininosuccinate lyase deficiency
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000694150.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The c.299T>C (p.Ile100Thr) in ASL gene is a missense change that alters a highly conserved nucleotide and 4/5 in silico tools predict deleterious … (more)
Variant summary: The c.299T>C (p.Ile100Thr) in ASL gene is a missense change that alters a highly conserved nucleotide and 4/5 in silico tools predict deleterious outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.00014 (17/118940 chrs tested). This frequency does not exceed the maximal expected allele frequency for a pathogenic variant in ASL gene (0.004). The results of functional studies are contradictious, depending on the expression system and ranging from ~90% of residual enzymatic activity in HEK293T to no detectable activity in bacterial cells. Since there is no information from the most reliable functional assay, such as citrulline incorporation was published at the time of evaluation, the results from the other functional assays mentioned above should be taken with caution. The variant was found homozygously or in compound heterozygosity in multiple affected individuals with established diagnosis of ASLD. Taken together, the variant was classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(Feb 13, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Argininosuccinate lyase deficiency
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000789572.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
|
|
|
Likely pathogenic
(Feb 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Argininosuccinate lyase deficiency
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002813811.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Oct 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Argininosuccinate lyase deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000819747.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 100 of the ASL protein (p.Ile100Thr). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 100 of the ASL protein (p.Ile100Thr). This variant is present in population databases (rs202142867, gnomAD 0.1%). This missense change has been observed in individuals with argininosuccinate lyase deficiency (PMID: 12384776, 18616627, 22231378). It is commonly reported in individuals of Finnish ancestry (PMID: 22231378). ClinVar contains an entry for this variant (Variation ID: 495379). 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 ASL protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ASL function (PMID: 21667091, 25778938, 31943503). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 17, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Argininosuccinate lyase deficiency
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004202961.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Likely pathogenic
(Jun 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001803171.2
First in ClinVar: Aug 21, 2021 Last updated: Jul 23, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21667091, 22231378, 31943503, 12384776, 25778938, 24166829, 35314707, 18616627) (less)
|
Comment:
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 100 of the ASL protein (p.Ile100Thr). This variant is present in population databases (rs202142867, gnomAD 0.1%). This missense change has been observed in individuals with argininosuccinate lyase deficiency (PMID: 12384776, 18616627, 22231378). It is commonly reported in individuals of Finnish ancestry (PMID: 22231378). ClinVar contains an entry for this variant (Variation ID: 495379). 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 ASL protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ASL function (PMID: 21667091, 25778938, 31943503). For these reasons, this variant has been classified as Pathogenic.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21667091, 22231378, 31943503, 12384776, 25778938, 24166829, 35314707, 18616627)
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:
Variant summary: The c.299T>C (p.Ile100Thr) in ASL gene is a missense change that alters a highly conserved nucleotide and 4/5 in silico tools predict deleterious outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.00014 (17/118940 chrs tested). This frequency does not exceed the maximal expected allele frequency for a pathogenic variant in ASL gene (0.004). The results of functional studies are contradictious, depending on the expression system and ranging from ~90% of residual enzymatic activity in HEK293T to no detectable activity in bacterial cells. Since there is no information from the most reliable functional assay, such as citrulline incorporation was published at the time of evaluation, the results from the other functional assays mentioned above should be taken with caution. The variant was found homozygously or in compound heterozygosity in multiple affected individuals with established diagnosis of ASLD. Taken together, the variant was classified as Pathogenic.
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 100 of the ASL protein (p.Ile100Thr). This variant is present in population databases (rs202142867, gnomAD 0.1%). This missense change has been observed in individuals with argininosuccinate lyase deficiency (PMID: 12384776, 18616627, 22231378). It is commonly reported in individuals of Finnish ancestry (PMID: 22231378). ClinVar contains an entry for this variant (Variation ID: 495379). 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 ASL protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ASL function (PMID: 21667091, 25778938, 31943503). For these reasons, this variant has been classified as Pathogenic.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21667091, 22231378, 31943503, 12384776, 25778938, 24166829, 35314707, 18616627)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| From genotype to phenotype: Early prediction of disease severity in argininosuccinic aciduria. | Zielonka M | Human mutation | 2020 | PMID: 31943503 |
| 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 |
| Hereditary urea cycle diseases in Finland. | Keskinen P | Acta paediatrica (Oslo, Norway : 1992) | 2008 | PMID: 18616627 |
| 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 |
Text-mined citations for rs202142867 ...
HelpThese 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
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.