Variant summary: ASS1 c.910C>T (p.Arg304Trp) results in a non-conservative amino acid change in the encoded protein sequence and it is predicted to involve in dimer-dimer interaction (Gao_2003). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251460 control chromosomes (gnomAD). c.910C>T has been reported in the literature in multiple individuals affected with Citrullinemia Type I (Kobayashi_1995, Gao_2003). These data indicate that the variant is very likely to be associated with disease. At least one publication reports this variant results in significantly decreasing normal activity (Gao_2003). One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_054012.4(ASS1):c.910C>T (p.Arg304Trp)
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.
(9)
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
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_054012.4(ASS1):c.910C>T (p.Arg304Trp)
Variation ID: 6330 Accession: VCV000006330.27
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q34.11 9: 130489404 (GRCh38) [ NCBI UCSC ] 9: 133364791 (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 Apr 8, 2013 Jun 17, 2024 Jan 5, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_054012.4:c.910C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_446464.1:p.Arg304Trp missense NM_000050.4:c.910C>T NP_000041.2:p.Arg304Trp missense NM_054012.3:c.910C>T NC_000009.12:g.130489404C>T NC_000009.11:g.133364791C>T NG_011542.1:g.49698C>T P00966:p.Arg304Trp - Protein change
- R304W
- Other names
- -
- Canonical SPDI
- NC_000009.12:130489403:C:T
-
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.
-
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00003
Exome Aggregation Consortium (ExAC) 0.00004
- 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. |
|||
| ASS1 | - | - |
GRCh38 GRCh37 |
819 | 871 | |
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 (6) |
criteria provided, multiple submitters, no conflicts
|
Jan 3, 2024 | RCV000006702.21 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 14, 2014 | RCV000723845.12 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 5, 2024 | RCV001376582.14 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Jul 14, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000225741.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Sex: mixed
|
|
|
Pathogenic
(Mar 12, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Citrullinuria
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001339034.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: ASS1 c.910C>T (p.Arg304Trp) results in a non-conservative amino acid change in the encoded protein sequence and it is predicted to involve in dimer-dimer … (more)
Variant summary: ASS1 c.910C>T (p.Arg304Trp) results in a non-conservative amino acid change in the encoded protein sequence and it is predicted to involve in dimer-dimer interaction (Gao_2003). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251460 control chromosomes (gnomAD). c.910C>T has been reported in the literature in multiple individuals affected with Citrullinemia Type I (Kobayashi_1995, Gao_2003). These data indicate that the variant is very likely to be associated with disease. At least one publication reports this variant results in significantly decreasing normal activity (Gao_2003). One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Citrullinemia
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046150.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This variant has been previously reported as a compound heterozygous change in patients with Citrullinemia (PMID: 7977368, 12815590, 23246278, 28302489). Functional studies have shown that … (more)
This variant has been previously reported as a compound heterozygous change in patients with Citrullinemia (PMID: 7977368, 12815590, 23246278, 28302489). Functional studies have shown that this missense variant affects normal function of ASS1 (PMID: 8792870). The c.910C>T (p.Arg304Trp) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (9/282796) and thus is presumed to be rare. The c.910C>T (p.Arg304Trp) variant affects a weakly conserved amino acid and in silico tools predict a discordant effect on protein function. Based on the available evidence, the c.910C>T (p.Arg304Trp) variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(Nov 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Citrullinemia type I
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002765079.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
This variant was identified as homozygous._x000D_ Criteria applied: PS3, PM3_STR, PM1, PM5, PM2_SUP, PP4
|
|
|
Pathogenic
(Jan 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Citrullinemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001202604.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 304 of the ASS1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 304 of the ASS1 protein (p.Arg304Trp). This variant is present in population databases (rs121908642, gnomAD 0.009%). This missense change has been observed in individual(s) with citrullinemia (PMID: 7977368, 12815590, 23246278, 28302489). ClinVar contains an entry for this variant (Variation ID: 6330). 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 ASS1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ASS1 function (PMID: 8792870). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jan 03, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Citrullinemia type I
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001163594.2
First in ClinVar: Feb 29, 2020 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Jul 05, 1990)
|
no assertion criteria provided
Method: literature only
|
CITRULLINEMIA, CLASSIC
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000026893.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 08, 2013 |
Comment on evidence:
Kobayashi et al. (1990) demonstrated a change in codon 304 in the ASS gene, CGG (arg) to TGG (trp), in a case of citrullinemia (215700).
|
|
|
Pathogenic
(Sep 22, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Citrullinemia type I
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002085101.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Citrullinemia type I
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000323096.2
First in ClinVar: Jun 28, 2015 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
This variant has been previously reported as a compound heterozygous change in patients with Citrullinemia (PMID: 7977368, 12815590, 23246278, 28302489). Functional studies have shown that this missense variant affects normal function of ASS1 (PMID: 8792870). The c.910C>T (p.Arg304Trp) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (9/282796) and thus is presumed to be rare. The c.910C>T (p.Arg304Trp) variant affects a weakly conserved amino acid and in silico tools predict a discordant effect on protein function. Based on the available evidence, the c.910C>T (p.Arg304Trp) variant is classified as Pathogenic.
Comment:
This variant was identified as homozygous._x000D_ Criteria applied: PS3, PM3_STR, PM1, PM5, PM2_SUP, PP4
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 304 of the ASS1 protein (p.Arg304Trp). This variant is present in population databases (rs121908642, gnomAD 0.009%). This missense change has been observed in individual(s) with citrullinemia (PMID: 7977368, 12815590, 23246278, 28302489). ClinVar contains an entry for this variant (Variation ID: 6330). 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 ASS1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ASS1 function (PMID: 8792870). 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:
Variant summary: ASS1 c.910C>T (p.Arg304Trp) results in a non-conservative amino acid change in the encoded protein sequence and it is predicted to involve in dimer-dimer interaction (Gao_2003). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251460 control chromosomes (gnomAD). c.910C>T has been reported in the literature in multiple individuals affected with Citrullinemia Type I (Kobayashi_1995, Gao_2003). These data indicate that the variant is very likely to be associated with disease. At least one publication reports this variant results in significantly decreasing normal activity (Gao_2003). One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This variant has been previously reported as a compound heterozygous change in patients with Citrullinemia (PMID: 7977368, 12815590, 23246278, 28302489). Functional studies have shown that this missense variant affects normal function of ASS1 (PMID: 8792870). The c.910C>T (p.Arg304Trp) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (9/282796) and thus is presumed to be rare. The c.910C>T (p.Arg304Trp) variant affects a weakly conserved amino acid and in silico tools predict a discordant effect on protein function. Based on the available evidence, the c.910C>T (p.Arg304Trp) variant is classified as Pathogenic.
Comment:
This variant was identified as homozygous._x000D_ Criteria applied: PS3, PM3_STR, PM1, PM5, PM2_SUP, PP4
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 304 of the ASS1 protein (p.Arg304Trp). This variant is present in population databases (rs121908642, gnomAD 0.009%). This missense change has been observed in individual(s) with citrullinemia (PMID: 7977368, 12815590, 23246278, 28302489). ClinVar contains an entry for this variant (Variation ID: 6330). 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 ASS1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ASS1 function (PMID: 8792870). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Citrullinemia Type I. | Adam MP | - | 2022 | PMID: 20301631 |
| Modelling urea-cycle disorder citrullinemia type 1 with disease-specific iPSCs. | Yoshitoshi-Uebayashi EY | Biochemical and biophysical research communications | 2017 | PMID: 28302489 |
| High prevalence of neonatal presentation in Korean patients with citrullinemia type 1, and their shared mutations. | Lee BH | Molecular genetics and metabolism | 2013 | PMID: 23246278 |
| Identification of 16 novel mutations in the argininosuccinate synthetase gene and genotype-phenotype correlation in 38 classical citrullinemia patients. | Gao HZ | Human mutation | 2003 | PMID: 12815590 |
| Nature and frequency of mutations in the argininosuccinate synthetase gene that cause classical citrullinemia. | Kobayashi K | Human genetics | 1995 | PMID: 7557970 |
| Characterization of human wild-type and mutant argininosuccinate synthetase proteins expressed in bacterial cells. | Shaheen N | Enzyme & protein | 1994 | PMID: 8792870 |
| Mutations in argininosuccinate synthetase mRNA of Japanese patients, causing classical citrullinemia. | Kobayashi K | American journal of human genetics | 1994 | PMID: 7977368 |
| Heterogeneity of mutations in argininosuccinate synthetase causing human citrullinemia. | Kobayashi K | The Journal of biological chemistry | 1990 | PMID: 2358466 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ASS1 | - | - | - | - |
Text-mined citations for rs121908642 ...
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 25, 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.