This sequence change creates a premature translational stop signal (p.Val349Cysfs*72) in the ASL gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs762010471, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with argininosuccinate lyase deficiency (PMID: 1705937, 16941645, 24166829). ClinVar contains an entry for this variant (Variation ID: 203629). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects ASL function (PMID: 31943503). Studies have shown that this premature translational stop signal results in skipping of exon 14 (also known as exon 13), but is expected to preserve the integrity of the reading-frame (PMID: 16941645). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000048.4(ASL):c.1045_1057del (p.Val349fs)
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
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.1045_1057del (p.Val349fs)
Variation ID: 203629 Accession: VCV000203629.16
- Type and length
-
Deletion, 13 bp
- Location
-
Cytogenetic: 7q11.21 7: 66089676-66089688 (GRCh38) [ NCBI UCSC ] 7: 65554663-65554675 (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 Jan 7, 2017 Nov 3, 2024 Oct 22, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000048.4:c.1045_1057del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000039.2:p.Val349fs frameshift NM_000048.3:c.1045_1057del13 NM_000048.3:c.1045_1057delGTCATCTCTACGC NM_001024943.2:c.1045_1057del NP_001020114.1:p.Val349fs frameshift NM_001024944.2:c.985_997del NP_001020115.1:p.Val329fs frameshift NM_001024946.2:c.967_979del NP_001020117.1:p.Val323fs frameshift NC_000007.14:g.66089678_66089690del NC_000007.13:g.65554665_65554677del NG_009288.1:g.18890_18902del - Protein change
- V329fs, V349fs, V323fs
- Other names
- -
- Canonical SPDI
- NC_000007.14:66089675:GCGTCATCTCTACGC:GC
-
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.
- -
- 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 |
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. |
|---|---|---|---|---|
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 22, 2024 | RCV000185780.6 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 3, 2024 | RCV000668476.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 8, 2023 | RCV001375026.2 |
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 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Argininosuccinate lyase deficiency
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000793086.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
|
|
|
Pathogenic
(Nov 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Argininosuccinate lyase deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000933200.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Val349Cysfs*72) in the ASL gene. RNA analysis indicates that this premature translational stop signal induces altered … (more)
This sequence change creates a premature translational stop signal (p.Val349Cysfs*72) in the ASL gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs762010471, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with argininosuccinate lyase deficiency (PMID: 1705937, 16941645, 24166829). ClinVar contains an entry for this variant (Variation ID: 203629). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects ASL function (PMID: 31943503). Studies have shown that this premature translational stop signal results in skipping of exon 14 (also known as exon 13), but is expected to preserve the integrity of the reading-frame (PMID: 16941645). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Oct 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000238713.10
First in ClinVar: Jul 18, 2015 Last updated: Nov 03, 2024 |
Comment:
Frameshift variant predicted to result in abnormal protein length as the last 116 amino acid(s) are replaced with 71 different amino acid(s), and other similar … (more)
Frameshift variant predicted to result in abnormal protein length as the last 116 amino acid(s) are replaced with 71 different amino acid(s), and other similar variants have been reported in HGMD; Gel-based analysis of mRNA derived from patient fibroblast cells harboring c.1045_1057del found that this variant frequently results in exon skipping (PMID: 1705937); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9045711, 21710918, 31943503, 1705937) (less)
|
|
|
Pathogenic
(Jun 16, 2021)
|
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: SCV001737746.1
First in ClinVar: Jun 23, 2021 Last updated: Jun 23, 2021 |
Comment:
Variant summary: ASL c.1045_1057del13 (p.Val349CysfsX72) 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.1045_1057del13 (p.Val349CysfsX72) 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 3.6e-05 in 250612 control chromosomes (gnomAD). c.1045_1057del13 has been reported in the literature in multiple individuals affected with Argininosuccinic Aciduria (Barbosa_1991, Walker_1997, Beck_2011, Balmer_2014, Zielonka_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports this deletion apparently causes exon skipping (Barbosa_1991). Four submitters (evaluation after 2014) cite the variant as pathogenic (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Mar 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental disorder
Affected status: yes
Allele origin:
germline
|
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Accession: SCV001572314.2
First in ClinVar: Apr 28, 2021 Last updated: Nov 11, 2023 |
|
|
|
Pathogenic
(Mar 03, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Argininosuccinate lyase deficiency
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004183478.2
First in ClinVar: Dec 24, 2023 Last updated: Jun 17, 2024 |
|
Comment:
Comment:
Frameshift variant predicted to result in abnormal protein length as the last 116 amino acid(s) are replaced with 71 different amino acid(s), and other similar variants have been reported in HGMD; Gel-based analysis of mRNA derived from patient fibroblast cells harboring c.1045_1057del found that this variant frequently results in exon skipping (PMID: 1705937); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9045711, 21710918, 31943503, 1705937)
Comment:
Variant summary: ASL c.1045_1057del13 (p.Val349CysfsX72) 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 3.6e-05 in 250612 control chromosomes (gnomAD). c.1045_1057del13 has been reported in the literature in multiple individuals affected with Argininosuccinic Aciduria (Barbosa_1991, Walker_1997, Beck_2011, Balmer_2014, Zielonka_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports this deletion apparently causes exon skipping (Barbosa_1991). Four submitters (evaluation after 2014) cite the variant as pathogenic (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was 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:
This sequence change creates a premature translational stop signal (p.Val349Cysfs*72) in the ASL gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs762010471, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with argininosuccinate lyase deficiency (PMID: 1705937, 16941645, 24166829). ClinVar contains an entry for this variant (Variation ID: 203629). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects ASL function (PMID: 31943503). Studies have shown that this premature translational stop signal results in skipping of exon 14 (also known as exon 13), but is expected to preserve the integrity of the reading-frame (PMID: 16941645). For these reasons, this variant has been classified as Pathogenic.
Comment:
Frameshift variant predicted to result in abnormal protein length as the last 116 amino acid(s) are replaced with 71 different amino acid(s), and other similar variants have been reported in HGMD; Gel-based analysis of mRNA derived from patient fibroblast cells harboring c.1045_1057del found that this variant frequently results in exon skipping (PMID: 1705937); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9045711, 21710918, 31943503, 1705937)
Comment:
Variant summary: ASL c.1045_1057del13 (p.Val349CysfsX72) 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 3.6e-05 in 250612 control chromosomes (gnomAD). c.1045_1057del13 has been reported in the literature in multiple individuals affected with Argininosuccinic Aciduria (Barbosa_1991, Walker_1997, Beck_2011, Balmer_2014, Zielonka_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports this deletion apparently causes exon skipping (Barbosa_1991). Four submitters (evaluation after 2014) cite the variant as pathogenic (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
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 |
| Mutations and polymorphisms in the human argininosuccinate lyase (ASL) gene. | Balmer C | Human mutation | 2014 | PMID: 24166829 |
| Rhode Island metabolic newborn screening: the effect of early identification. A case report of argininosuccinic aciduria (ASA). | Beck NM | Medicine and health, Rhode Island | 2011 | PMID: 21710918 |
| Deletion hotspot in the argininosuccinate lyase gene: association with topoisomerase II and DNA polymerase alpha sites. | Christodoulou J | Human mutation | 2006 | PMID: 16941645 |
| 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 |
| Intragenic complementation at the human argininosuccinate lyase locus. Identification of the major complementing alleles. | Walker DC | The Journal of biological chemistry | 1997 | PMID: 9045711 |
| Analysis of naturally occurring and site-directed mutations in the argininosuccinate lyase gene. | Barbosa P | The Journal of biological chemistry | 1991 | PMID: 1705937 |
Text-mined citations for rs796051933 ...
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 Nov 03, 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.