NM_054012.4(ASS1):c.815G>A (p.Arg272His) AND Citrullinemia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 14, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003226684.1

Allele description [Variation Report for NM_054012.4(ASS1):c.815G>A (p.Arg272His)]

NM_054012.4(ASS1):c.815G>A (p.Arg272His)

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.815G>A (p.Arg272His)

HGVS:

NC_000009.12:g.130480426G>A
NG_011542.1:g.40720G>A
NM_000050.4:c.815G>A
NM_054012.4:c.815G>AMANE SELECT
NP_000041.2:p.Arg272His
NP_446464.1:p.Arg272His
NC_000009.11:g.133355813G>A

Protein change:

R272H

Links:

dbSNP: rs768215008

NCBI 1000 Genomes Browser:

rs768215008

Molecular consequence:

NM_000050.4:c.815G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_054012.4:c.815G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Citrullinemia
Synonyms:: Citrullinuria
Identifiers:: MONDO: MONDO:0015991; MedGen: C0175683; Human Phenotype Ontology: HP:0032397

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003922715	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 14, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27287393, 18925679, 31469252 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003922715

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Mar 14, 2023)

germline

clinical testing

PubMed (3)
[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

Kinetic mutations in argininosuccinate synthetase deficiency: characterisation and in vitro correction by substrate supplementation.

Diez-Fernandez C, Wellauer O, Gemperle C, Rüfenacht V, Fingerhut R, Häberle J.

J Med Genet. 2016 Oct;53(10):710-9. doi: 10.1136/jmedgenet-2016-103937. Epub 2016 Jun 10.

PubMed [citation]

PMID:: 27287393

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

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003922715.1

#	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.815G>A (p.Arg272His) results in a non-conservative amino acid change in 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 8e-06 in 251230 control chromosomes (gnomAD). c.815G>A has been reported in the literature in multiple individuals affected with Citrullinemia (example: Dimmock_2008, Diez-Fernandez_2016, and Zielonka_2019). These data indicate that the variant is very likely to be associated with disease. Multiple reports have provided experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (Diez-Fernandez_2016, and Zielonka_2019). A different variant affecting the same codon (c.814C>T (p.Arg272Cys) is classified pathogenic in ClinVar (ID 371132). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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: Apr 15, 2024

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