NM_054012.4(ASS1):c.835C>T (p.Arg279Ter) AND Citrullinemia type I

Germline classification:: Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:: Mar 9, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000006705.26

Allele description [Variation Report for NM_054012.4(ASS1):c.835C>T (p.Arg279Ter)]

NM_054012.4(ASS1):c.835C>T (p.Arg279Ter)

Gene:

ASS1:argininosuccinate synthase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q34.11

Genomic location:

Preferred name:

NM_054012.4(ASS1):c.835C>T (p.Arg279Ter)

HGVS:

NC_000009.12:g.130480446C>T
NG_011542.1:g.40740C>T
NM_000050.4:c.835C>T
NM_054012.4:c.835C>TMANE SELECT
NP_000041.2:p.Arg279Ter
NP_446464.1:p.Arg279Ter
NC_000009.11:g.133355833C>T

Protein change:

R279*; ARG279TER

Links:

OMIM: 603470.0013; dbSNP: rs121908645

NCBI 1000 Genomes Browser:

rs121908645

Molecular consequence:

NM_000050.4:c.835C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_054012.4:c.835C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Citrullinemia type I (CTNL1)
Synonyms:: Classic citrullinemia; ASS deficiency; Citrullinemia 1; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008988; MedGen: C4721769; Orphanet: 247525; OMIM: 215700

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000026896	OMIM	no assertion criteria provided	Pathogenic (Sep 1, 2001)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000220625	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Aug 22, 2014)	unknown	literature only	PubMed (6) [See all records that cite these PMIDs] 11571557, 16475226, 12815590, 18925679, 24508627, 19006241 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV001156647	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Aug 29, 2019)	germline	clinical testing	Citation Link,
SCV001163592	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 9, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001338439	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 30, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12815590, 16475226, 11571557 Citation Link,
SCV001453090	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002809909	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 28, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003814426	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 21, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only

Citations

PubMed

The role of molecular testing and enzyme analysis in the management of hypomorphic citrullinemia.

Dimmock DP, Trapane P, Feigenbaum A, Keegan CE, Cederbaum S, Gibson J, Gambello MJ, Vaux K, Ward P, Rice GM, Wolff JA, O'Brien WE, Fang P.

Am J Med Genet A. 2008 Nov 15;146A(22):2885-90. doi: 10.1002/ajmg.a.32527. Erratum in: Am J Med Genet A. 2010 Apr;152A(4):1061.

PubMed [citation]

PMID:: 18925679
PMCID:: PMC2597641

Molecular genetics of citrullinemia types I and II.

Woo HI, Park HD, Lee YW.

Clin Chim Acta. 2014 Apr 20;431:1-8. doi: 10.1016/j.cca.2014.01.032. Epub 2014 Feb 5. Review.

PubMed [citation]

PMID:: 24508627

See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000026896.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a citrullinemia (215700) patient carrying an RNA-negative allele, Li et al. (2001) described a C-to-T transition at nucleotide 835 in the cDNA of the ASS gene, converting the CGA arginine codon to a TGA termination codon within exon 12 (R279X). The patient was compound heterozygous for the R279X mutation and the IVS6-2A-G mutation (603470.0003). There was no indication of the R279X mutation leading to altered splicing, and the most likely defect responsible for the mRNA reduction appeared to be nonsense-mediated mRNA decay affecting the abundance of nucleus-associated mRNA. It was estimated that mRNA from the R279X allele was less than 2% of the normal level.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000220625.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (6)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001156647.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The ASS1 c.835C>T; p.Arg279Ter variant (rs121908645) has been described in the homozygous and compound heterozygous states in individuals diagnosed with citrullinemia (Gao 2003, Kleijer 2006, Li 2001). It is reported as pathogenic and likely pathogenic in ClinVar (Variation ID: 6333) and observed in the general population at a low overall frequency of 0.0024% (6/245706 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, RNA analysis of this variant in skin fibroblasts from an affected patient demonstrated an RNA-negative allele in which no stable mRNA was detected (Li 2001). Based on available information, this variant is considered pathogenic. References: Gao H et al. Identification of 16 novel mutations in the argininosuccinate synthetase gene and genotype-phenotype correlation in 38 classical citrullinemia patients. Hum Mutat. 2003 Jul;22(1):24-34. Kleijer W et al. Prenatal diagnosis of citrullinemia and argininosuccinic aciduria: evidence for a transmission ratio distortion in citrullinemia. Prenat Diagn. 2006 Mar;26(3):242-7. Li C et al. A nonsense mutation is responsible for the RNA-negative phenotype in human citrullinaemia. Eur J Hum Genet. 2001 Sep;9(9):685-9.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001163592.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001338439.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: ASS1 c.835C>T (p.Arg279X) 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 2.4e-05 in 250820 control chromosomes. c.835C>T has been reported in the literature in multiple individuals affected with Citrullinemia Type I (examples- Li_2001, Gao_2003, Kleijer_2006). These data indicate that the variant is very likely to be associated with disease. No stable mRNA was detected from the allele with the variant in RNA isolated from patient skin fibroblasts, presumably due to nonsense-mediated decay (Li_2001). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001453090.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002809909.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003814426.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

Relating variation to medicine