NM_054012.4(ASS1):c.970+5G>A AND Citrullinemia type I

Germline classification:: Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:: Jan 3, 2022
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:: RCV000256325.15

Allele description [Variation Report for NM_054012.4(ASS1):c.970+5G>A]

NM_054012.4(ASS1):c.970+5G>A

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.970+5G>A

HGVS:

NC_000009.12:g.130489469G>A
NG_011542.1:g.49763G>A
NM_000050.4:c.970+5G>A
NM_054012.4:c.970+5G>AMANE SELECT
NC_000009.11:g.133364856G>A
NM_054012.4:c.970+5G>A

Links:

OMIM: 603470.0017; dbSNP: rs372128852

NCBI 1000 Genomes Browser:

rs372128852

Molecular consequence:

NM_000050.4:c.970+5G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_054012.4:c.970+5G>A - intron variant - [Sequence Ontology: SO:0001627]

Observations:

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
SCV000026900	OMIM	no assertion criteria provided	Pathogenic (Apr 1, 2002)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000323100	GeneReviews	no assertion criteria provided	Pathogenic (Sep 1, 2016)	germline	literature only	Citation Link,
SCV000790673	Counsyl	no assertion criteria provided	Likely pathogenic (Mar 31, 2017)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 7557970, 11941481, 12815590, 28111830, 27287393
SCV000893798	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001163599	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001338489	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 2, 2020)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 24508627, 27287393, 28111830, 7557970, 12815590, 11941481 Citation Link,
SCV002024389	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 11, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002059126	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] PMID:7557970

Help

Summary from all submissions

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

Citations

PubMed

Molecular genetics of citrullinemia types I and II.

Woo HI, Park HD, Lee YW.

Clin Chim Acta. 2014 Apr 20;431:1-8. doi: 10.1016/j.cca.2014.01.032. Epub 2014 Feb 5. Review.

PubMed [citation]

PMID:: 24508627

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

See all PubMed Citations (7)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From OMIM, SCV000026900.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

See 603470.0014 and Haberle et al. (2002).

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

From GeneReviews, SCV000323100.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	not provided

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

From Counsyl, SCV000790673.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

#	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 Fulgent Genetics, Fulgent Genetics, SCV000893798.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001163599.1

#	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	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, SCV001338489.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: ASS1 c.970+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict that the variant abolishes or weakens a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (e.g. Kobayashi_1995). The variant allele was found at a frequency of 1.6e-05 in 251104 control chromosomes (gnomAD). c.970+5G>A has been reported in the literature in multiple individuals affected with Citrullinemia Type I (e.g. Kobayashi_1995, Haberle_2002, Gao_2003, Diez-Fernandez_2016). These data indicate that the variant is very likely to be associated with disease. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. 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

From Revvity Omics, Revvity, SCV002024389.3

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002059126.1

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

Description

The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (PMID_11941481, ClinVar ID: VCV000265962). The variant has been reported to be in trans as homozygous in at least one similarly affected unrelated individual (PMID: 7557970, PM3_P). In silico prediction tools predicted that this variant influenced pre-mRNA splicing, resulting in aberrant splicing (SPLICEAI: 0.92>=0.8, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000018, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

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

Last Updated: Apr 15, 2024

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