NM_054012.4(ASS1):c.571G>A (p.Glu191Lys) AND Citrullinemia type I

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Mar 25, 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:: RCV000190357.9

Allele description [Variation Report for NM_054012.4(ASS1):c.571G>A (p.Glu191Lys)]

NM_054012.4(ASS1):c.571G>A (p.Glu191Lys)

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.571G>A (p.Glu191Lys)

HGVS:

NC_000009.12:g.130471489G>A
NG_011542.1:g.31783G>A
NM_000050.4:c.571G>A
NM_054012.4:c.571G>AMANE SELECT
NP_000041.2:p.Glu191Lys
NP_446464.1:p.Glu191Lys
NC_000009.11:g.133346876G>A
NM_054012.4:c.571G>A
P00966:p.Glu191Lys

Protein change:

E191K

Links:

UniProtKB: P00966#VAR_015899; dbSNP: rs777828000

NCBI 1000 Genomes Browser:

rs777828000

Molecular consequence:

NM_000050.4:c.571G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_054012.4:c.571G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Citrullinemia type I (CTNL1)
Synonyms:: ASS DEFICIENCY; argininosuccinate synthetase deficiency
Identifiers:: MONDO: MONDO:0008988; MedGen: C4721769; Orphanet: 247525; OMIM: 215700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000153773	Quest Diagnostics Nichols Institute San Juan Capistrano	no assertion criteria provided	Pathogenic (May 25, 2014)	inherited	clinical testing	PubMed (2) [See all records that cite these PMIDs] 12815590, 19006241
SCV000796863	Counsyl	no assertion criteria provided	Likely pathogenic (Jan 3, 2018)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28111830, 24713661, 12815590
SCV001163229	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 25, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001453086	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV004812359	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 11, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 12815590, 20301396, 20301631, 24713661, 28111830, 33190319, 36685561, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	inherited	yes	1	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

Citations

PubMed

Mutations and polymorphisms in the human argininosuccinate synthetase (ASS1) gene.

Engel K, Höhne W, Häberle J.

Hum Mutat. 2009 Mar;30(3):300-7. doi: 10.1002/humu.20847. Review.

PubMed [citation]

PMID:: 19006241

Identification of 16 novel mutations in the argininosuccinate synthetase gene and genotype-phenotype correlation in 38 classical citrullinemia patients.

Gao HZ, Kobayashi K, Tabata A, Tsuge H, Iijima M, Yasuda T, Kalkanoglu HS, Dursun A, Tokatli A, Coskun T, Trefz FK, Skladal D, Mandel H, Seidel J, Kodama S, Shirane S, Ichida T, Makino S, Yoshino M, Kang JH, Mizuguchi M, Barshop BA, et al.

Hum Mutat. 2003 Jul;22(1):24-34.

PubMed [citation]

PMID:: 12815590

See all PubMed Citations (9)

Details of each submission

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000153773.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

Homozygous missense mutation in the ASS1 gene.

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

From Counsyl, SCV000796863.2

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

Description

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

#	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 Baylor Genetics, SCV001163229.2

#	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 Natera, Inc., SCV001453086.1

#	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 Molecular Genetics, Royal Melbourne Hospital, SCV004812359.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change in ASS1 is predicted to replace glutamic acid with lysine at codon 191, p.(Glu191Lys). The glutamic acid residue is highly conserved (84/84 vertebrates, UCSC), and is located in the citrulline/aspartate binding domain (PMID: 12815590). There is a small physicochemical difference between glutamic acid and lysine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.01% (3/24,962 alleles) in the African/African American population, which is consistent with a recessive disease. This variant has been detected in at least ten individuals with citrullinaemia. Of those individuals, seven individuals were homozygous and three were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (PMID: 12815590, 24713661, 28111830, 33190319, 36685561). At least one of these patients displayed a marked elevation in plasma citrulline concentrations, which is highly specific for ASS1 deficiency (PMID: 20301396, 20301631). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.973). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM3_Strong, PP3_Moderate, PM2_Supporting, PP4.

#	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: Jun 29, 2025

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