ClinVar Genomic variation as it relates to human health
NM_054012.4(ASS1):c.970G>A (p.Gly324Ser)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_054012.4(ASS1):c.970G>A (p.Gly324Ser)
Variation ID: 6327 Accession: VCV000006327.52
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 9q34.11 9: 130489464 (GRCh38) [ NCBI UCSC ] 9: 133364851 (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 Oct 8, 2024 Mar 25, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_054012.4:c.970G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_446464.1:p.Gly324Ser missense NM_000050.4:c.970G>A NP_000041.2:p.Gly324Ser missense NC_000009.12:g.130489464G>A NC_000009.11:g.133364851G>A NG_011542.1:g.49758G>A - Protein change
- G324S
- Other names
- -
- Canonical SPDI
- NC_000009.12:130489463:G:A
-
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) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Exome Aggregation Consortium (ExAC) 0.00005
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 |
814 | 866 |
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 (9) |
criteria provided, multiple submitters, no conflicts
|
Mar 25, 2024 | RCV000006699.26 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 16, 2024 | RCV001376631.10 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jul 1, 2021 | RCV001531743.20 | |
ASS1-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Dec 2, 2023 | RCV003934804.3 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Jan 17, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Citrullinemia
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000593461.1
First in ClinVar: May 27, 2015 Last updated: May 27, 2015 |
|
|
Pathogenic
(Jan 31, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Citrullinemia type I
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368808.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3,PP3,PP4.
|
|
Pathogenic
(Oct 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Citrullinemia type I
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV002012159.1
First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000006327.8, PS1). It is … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000006327.8, PS1). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000358, PM2). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID:16475226, 12815590 PM3). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97, 3Cnet: 0.990, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Brain atrophy (present) , Delayed speech and language development (present) , Elevated plasma citrulline (present) , Delayed gross motor development (present) , Seizure (present) , … (more)
Brain atrophy (present) , Delayed speech and language development (present) , Elevated plasma citrulline (present) , Delayed gross motor development (present) , Seizure (present) , Intellectual disability (present) (less)
|
|
Pathogenic
(Aug 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Citrullinemia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002572032.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
Variant summary: ASS1 c.970G>A (p.Gly324Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: ASS1 c.970G>A (p.Gly324Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251184 control chromosomes. c.970G>A has been reported in the literature in numerous individuals affected with Citrullinemia Type I, in the homozygous and compound heterozygous state (examples: Gao_2003, Haberle_2003, Lee_2013, etc). These data indicate that the variant is very likely to be associated with disease. Six 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Apr 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Citrullinemia type I
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002787433.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Pathogenic
(Dec 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Citrullinemia type I
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
|
Centre de Genetique Humaine, Institut de Pathologie et de Genetique
Accession: SCV004190118.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
Comment:
The c.970G>A impacts a highly conserved nucleotide (phyloP: 9.18) and a highly conserved amino acid (down to the yeast). It has 2 occurrences in gnomAD … (more)
The c.970G>A impacts a highly conserved nucleotide (phyloP: 9.18) and a highly conserved amino acid (down to the yeast). It has 2 occurrences in gnomAD v4. Prediction tools pedict a deleterious effect (20/21), CADD : 34, REVEL 0.970. It is predicted to alter splicing (SpliceAI : donor loss 0.67). In vitro data revealed complete loss of enzyme activity (residual activity <2%) (PMID: 18473344). Despite having a severe impact on enzyme activity in vitro, the variant was reported in two asymptomatic patients with citrullinemia type 1, one was hmozygote for the variant and the second was compound heterozygote with the c.40G>A p.(Gly14Ser) variant (PMID: 14680976). It was also reported in a Korean cohort with neonatal onset (1 to 16d, in trans with c.421-2A>G) or later onset (3m, in trans with c.421-2A>G or c.1128-6_1188dup67) (PMID: 23246278). Our patient (mild form of ASSD) carries the c.808G>C variant in cis with c.206T>C, inherited from his father, and in trans with c.970G>A, inherited from his mother. Intriguingly, the paternal allele of our patient is composed of the two variants reported in PMID: 11708871, which are presumably in trans in the published patient (severe case). There is second published patient who also carries the same two variants with no reported segregation (PMID: 12815590). In gnomAD, c.206T>C and c.808G>C have the same number of occurrences (v2.1.1 : 2-2, v4.0.0 : 5-5). These two variant might be on the same haplotype and we postulate that there is a third variant in trans that was not found in the first published case (PMID: 11708871). This would explain why our patient has a mild phenotype resulting from an hypomorphic allele c.970G>A (PMID: 14680976) + a severe allele [c.206T>C;c.808G>C]. (less)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Caucasian
Geographic origin: Belgium
Comment on evidence:
Newborn screening showed elevated citrulline (200 μM N 4-25) confirmed on plasma amino acid chromatogram (Cit 545 μM, Gln 721 μM, Arg 20 μmol/L). He … (more)
Newborn screening showed elevated citrulline (200 μM N 4-25) confirmed on plasma amino acid chromatogram (Cit 545 μM, Gln 721 μM, Arg 20 μmol/L). He follows a protein restricted diet (1 g/kg/d) with low dose arginine supplementation (100 mg/kg/d) and he has been sick multiple times without acute decompensation. He has never received any scavenger therapy (3 y.o.). Last chromatogram showed : Cit 678 µM N 18-50, Gln : 481 µM N 373-709, Arg 75 µM N 38-98. He has a mild form of ASSD. Yet, the variants that he caries have previously been associated with severe phenotypes. (less)
|
|
Pathogenic
(Mar 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Citrullinemia type I
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001163598.2
First in ClinVar: Feb 28, 2020 Last updated: Jun 17, 2024 |
|
|
Likely pathogenic
(Jul 19, 2014)
|
criteria provided, single submitter
Method: literature only
|
Citrullinemia type I
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220532.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
|
Pathogenic
(Jan 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Citrullinemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000630068.10
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 324 of the ASS1 protein (p.Gly324Ser). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 324 of the ASS1 protein (p.Gly324Ser). This variant also falls at the last nucleotide of exon 13, which is part of the consensus splice site for this exon. This variant is present in population databases (rs121908639, gnomAD 0.01%). This missense change has been observed in individual(s) with citrullinemia (PMID: 2358466, 11211875, 12815590, 14680976, 18473344). ClinVar contains an entry for this variant (Variation ID: 6327). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Jul 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001747007.19
First in ClinVar: Jul 10, 2021 Last updated: Oct 08, 2024 |
Number of individuals with the variant: 3
|
|
Pathogenic
(Apr 04, 2013)
|
no assertion criteria provided
Method: literature only
|
CITRULLINEMIA, CLASSIC
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000026890.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 08, 2013 |
Comment on evidence:
Kobayashi et al. (1989) demonstrated change in codon 324 in the ASS gene, GGT (gly) to AGT (ser), in a case of citrullinemia (215700).
|
|
Pathogenic
(Jan 20, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Citrullinemia type I
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002085106.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
Pathogenic
(Dec 02, 2023)
|
no assertion criteria provided
Method: clinical testing
|
ASS1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004752051.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The ASS1 c.970G>A variant is predicted to result in the amino acid substitution p.Gly324Ser. This variant has been reported in the homozygous state or heterozygous … (more)
The ASS1 c.970G>A variant is predicted to result in the amino acid substitution p.Gly324Ser. This variant has been reported in the homozygous state or heterozygous state with a second causative ASS1 variant in multiple individuals with citrullinaemia type I; in at least one patient, it was found in trans with a pathogenic variant (Kobayashi et al. 1990. PubMed ID: 2358466; Hong et al. 2000. PubMed ID: 10987146; Gao et al. 2003. PubMed ID: 12815590; Häberle et al. 2003. PubMed ID: 14680976; Bijarnia-Mahay et al. 2018. PubMed ID: 30285816). In one study of a group of patients with classic citrullinemia, it was found on 4 of 45 independent alleles, though additional genetic information was not provided on those patients (Berning et al. 2008. PubMed ID: 18473344). In an E. coli expression study, the p.Gly324Ser substitution reduced enzyme activity to <2% (Berning et al. 2008. PubMed ID: 18473344). Additionally, the c.970G nucleotide is the last nucleotide in exon 13 of the ASS1 gene, and the c.970G>A variant is predicted to impact splicing at the adjacent canonical splice donor site (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. In summary, this variant is interpreted as pathogenic. (less)
|
|
click to load more click to collapse |
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
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 |
Investigation of citrullinemia type I variants by in vitro expression studies. | Berning C | Human mutation | 2008 | PMID: 18473344 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Prenatal diagnosis of citrullinemia and argininosuccinic aciduria: evidence for a transmission ratio distortion in citrullinemia. | Kleijer WJ | Prenatal diagnosis | 2006 | PMID: 16475226 |
Mild citrullinemia in Caucasians is an allelic variant of argininosuccinate synthetase deficiency (citrullinemia type 1). | Häberle J | Molecular genetics and metabolism | 2003 | PMID: 14680976 |
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 |
The first successful prenatal diagnosis on a Korean family with citrullinemia. | Hong KM | Molecules and cells | 2000 | PMID: 11211875 |
Mutation analysis of Korean patients with citrullinemia. | Hong KM | Molecules and cells | 2000 | PMID: 10987146 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Heterogeneity of mutations in argininosuccinate synthetase causing human citrullinemia. | Kobayashi K | The Journal of biological chemistry | 1990 | PMID: 2358466 |
Kobayashi, K., Jackson, M. J., Tick, D. B., O'Brien, W. E., Beaudet, A. L. Characterization of nine mutant alleles causing citrullinemia. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A201-only, 1989. | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs121908639 ...
HelpRecord last updated Oct 13, 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.