NM_054012.4(ASS1):c.805G>A (p.Val269Met) AND Citrullinemia

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 17, 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:: RCV001290023.7

Allele description [Variation Report for NM_054012.4(ASS1):c.805G>A (p.Val269Met)]

NM_054012.4(ASS1):c.805G>A (p.Val269Met)

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.805G>A (p.Val269Met)

HGVS:

NC_000009.12:g.130480416G>A
NG_011542.1:g.40710G>A
NM_000050.4:c.805G>A
NM_054012.4:c.805G>AMANE SELECT
NP_000041.2:p.Val269Met
NP_446464.1:p.Val269Met
NC_000009.11:g.133355803G>A
P00966:p.Val269Met

Protein change:

V269M

Links:

UniProtKB: P00966#VAR_015901; dbSNP: rs370595480

NCBI 1000 Genomes Browser:

rs370595480

Molecular consequence:

NM_000050.4:c.805G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_054012.4:c.805G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Galm galactose mutarotase [Mus musculus]
Galm galactose mutarotase [Mus musculus]
Gene ID:319625

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000957991	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 17, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12815590, 14680976, 28492532
SCV002555957	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jun 2, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12684898, 32778825, 33851512, 31469252 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000957991

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 17, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002555957

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Jun 2, 2022)

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

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

Mild citrullinemia in Caucasians is an allelic variant of argininosuccinate synthetase deficiency (citrullinemia type 1).

Häberle J, Pauli S, Schmidt E, Schulze-Eilfing B, Berning C, Koch HG.

Mol Genet Metab. 2003 Nov;80(3):302-6.

PubMed [citation]

PMID:: 14680976

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000957991.6

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

Description

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 269 of the ASS1 protein (p.Val269Met). This variant is present in population databases (rs370595480, gnomAD 0.01%). This missense change has been observed in individual(s) with mild citrullinemia type 1 (PMID: 12815590, 14680976; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 193968). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ASS1 protein function. 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, SCV002555957.1

#	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.805G>A (p.Val269Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251314 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ASS1 causing Citrullinemia Type I (5.2e-05 vs 0.0041), allowing no conclusion about variant significance. c.805G>A has been reported in the literature in individuals affected with citrullinemia or urea cycle disorders. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating protein residual activity, however, does not allow convincing conclusions about the variant effect (Zielonka_2019). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Pathogenic n=1, likely pathogenic n=2, VUS n=2). Based on the evidence outlined above, the variant was classified as likely 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: Sep 29, 2024

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