NM_054012.4(ASS1):c.-4C>T AND Citrullinemia type I

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: Apr 11, 2023
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:: RCV000541100.14

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

NM_054012.4(ASS1):c.-4C>T

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.-4C>T

HGVS:

NC_000009.12:g.130452225C>T
NG_011542.1:g.12519C>T
NM_000050.4:c.-4C>T
NM_054012.4:c.-4C>TMANE SELECT
NC_000009.11:g.133327612C>T
NM_054012.3:c.-4C>T

Links:

dbSNP: rs138350285

NCBI 1000 Genomes Browser:

rs138350285

Molecular consequence:

NM_000050.4:c.-4C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_054012.4:c.-4C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001328934	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001737167	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 18, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002060122	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Uncertain significance (Oct 1, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002082214	Natera, Inc.	no assertion criteria provided	Uncertain significance (Jun 21, 2021)	germline	clinical testing
SCV004812374	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 11, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28111830, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	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
not provided	germline	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

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 (3)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001328934.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	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 Genome-Nilou Lab, SCV001737167.1

#	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	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV002060122.2

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

Description

NM_000050.4(ASS1):c.-4C>T is a 5' non-coding variant classified as a variant of uncertain significance in the context of citrullinemia type 1. c.-4C>T has been observed in a case with relevant disease (PMID: 28111830). Functional assessments of this variant are not available in the literature. c.-4C>T has been observed in population frequency databases (gnomAD: SAS 0.18%). In summary, there is insufficient evidence to classify NM_000050.4(ASS1):c.-4C>T as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.

#	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., SCV002082214.1

#	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, SCV004812374.1

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

Description

This sequence change in ASS1 is located in the 5' untranslated region. It introduces an alternative initiation codon and alters the Kozak consensus sequence, which plays an essential role in protein translation initiation. No functional assays have been reported to assess if the variant affects protein translation. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.18% (55/30,574 alleles) in the South Asian population. This variant has been reported as likely pathogenic, a variant of uncertain significance, and likely benign (ClinVar ID: 203632). This variant has been observed with a variant of uncertain significance in an individual with citrullinaemia (PMID: 28111830). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: none.

#	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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