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

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 28, 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:: RCV001376580.7

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]

Condition(s)

Name:: Citrullinemia
Identifiers:: MONDO: MONDO:0015991; MedGen: C0175683; OMIM: PS215700

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
SCV001211484	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 28, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12815590, 24713661, 28111830, 28492532
SCV004804496	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 12, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 28111830, 12815590, 31469252, 24713661 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001211484

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 28, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004804496

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jan 12, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Mutations in the Human Argininosuccinate Synthetase (ASS1) Gene, Impact on Patients, Common Changes, and Structural Considerations.

Diez-Fernandez C, Rüfenacht V, Häberle J.

Hum Mutat. 2017 May;38(5):471-484. doi: 10.1002/humu.23184. Epub 2017 Feb 15. Review.

PubMed [citation]

PMID:: 28111830

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001211484.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 191 of the ASS1 protein (p.Glu191Lys). This variant is present in population databases (rs777828000, gnomAD 0.01%). This missense change has been observed in individual(s) with citrullinemia (PMID: 12815590, 24713661, 28111830; Invitae). ClinVar contains an entry for this variant (Variation ID: 208153). 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%. For these reasons, this variant has been 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004804496.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: ASS1 c.571G>A (p.Glu191Lys) results in a conservative amino acid change located in the Arginosuccinate synthase C-terminal domain (IPR048268) of the encoded protein sequence. 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 2e-05 in 251436 control chromosomes (gnomAD). c.571G>A has been reported in the literature in multiple individuals affected with Citrullinemia Type I (Gao_2003, Sahoo_2015, Diez-Fernandez_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant showed less than 10% of WT activity in transfected cells (Zielonka_2019). The following publications have been ascertained in the context of this evaluation (PMID: 28111830, 12815590, 24713661, 31469252). ClinVar contains an entry for this variant (Variation ID: 208153). 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

Last Updated: Jun 29, 2025

ClinVar

Relating variation to medicine