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

Germline classification:
Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:
Jan 12, 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:
RCV000256325.16

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:
1

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000026900OMIM
no assertion criteria provided
Pathogenic
(Apr 1, 2002)
germlineliterature only

PubMed (1)
[See all records that cite this PMID]

SCV000323100GeneReviews
no assertion criteria provided
Pathogenic
(Sep 1, 2016)
germlineliterature only

Citation Link,

SCV000790673Counsyl
no assertion criteria provided
Likely pathogenic
(Mar 31, 2017)
unknownclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV000893798Fulgent Genetics, Fulgent Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Oct 31, 2018)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001163599Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jan 12, 2024)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001338489Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Pathogenic
(Apr 2, 2020)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV002024389Revvity Omics, Revvity
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Mar 11, 2021)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV0020591263billion
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Jan 3, 2022)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

PMID:7557970

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot provided1not providedliterature only, clinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

See 603470.0014 and Haberle et al. (2002).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From GeneReviews, SCV000323100.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature onlynot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Counsyl, SCV000790673.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Fulgent Genetics, Fulgent Genetics, SCV000893798.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV001163599.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001338489.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Revvity Omics, Revvity, SCV002024389.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From 3billion, SCV002059126.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided

Last Updated: Jul 15, 2024