NM_054012.4(ASS1):c.892del (p.Glu298fs) AND Citrullinemia type I

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Sep 18, 2017)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000169181.9

Allele description [Variation Report for NM_054012.4(ASS1):c.892del (p.Glu298fs)]

NM_054012.4(ASS1):c.892del (p.Glu298fs)

Gene:
ASS1:argininosuccinate synthase 1 [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
9q34.11
Genomic location:
Preferred name:
NM_054012.4(ASS1):c.892del (p.Glu298fs)
HGVS:
  • NC_000009.12:g.130489386del
  • NG_011542.1:g.49680del
  • NM_000050.4:c.892del
  • NM_054012.4:c.892delMANE SELECT
  • NP_000041.2:p.Glu298fs
  • NP_446464.1:p.Glu298fs
  • NC_000009.11:g.133364773del
  • NC_000009.11:g.133364773delG
  • NM_000050.4:c.892delG
  • NM_054012.3:c.892delG
Protein change:
E298fs
Links:
dbSNP: rs770362721
NCBI 1000 Genomes Browser:
rs770362721
Molecular consequence:
  • NM_000050.4:c.892del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_054012.4:c.892del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:
Citrullinemia type I (CTNL1)
Synonyms:
Classic citrullinemia; Citrullinuria; ASS deficiency; 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
SCV000220418Counsylcriteria provided, single submitter
Likely pathogenic
(Jun 16, 2014)
unknownliterature only

PubMed (4)
[See all records that cite these PMIDs]

Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015),

Citation Link,

SCV000694166Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(May 4, 2016)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000915271Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Pathogenic
(Sep 18, 2017)
germlineclinical testing

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

Citation Link,

SCV001163593Baylor Geneticscriteria provided, single submitter
Pathogenicgermlineclinical testing

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

SCV001453091Natera, Inc.no assertion criteria providedPathogenic
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

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
See all PubMed Citations (7)

Details of each submission

From Counsyl, SCV000220418.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000694166.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: The c.892delG variant is predicted to cause a frameshift, which alters the proteins amino acid sequence beginning at position 298 and leads to a premature termination codon 17 amino acids downstream. It is predicted to cause a truncated or absent ASS1 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.R389Qfs). One in-silico tool predicts damaging outcome for this variant. This variant is found in 1/121396 control chromosomes at a frequency of 0.0000082, which does not exceed maximal expected frequency of a pathogenic allele (0.0040825). This variant has been reported in at least two affected individuals. In addition, one clinical laboratory classified this variant as likely pathogenic, without evidence to independently evaluate. Taken together, this variant was classified as pathogenic.

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

From Illumina Clinical Services Laboratory,Illumina, SCV000915271.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

The ASS1 c.892delG (p.Glu298ArgfsTer18) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Glu298ArgfsTer18 variant has been reported in three studies in which it has been found in a compound heterozygous state in four individuals with citrullinemia including two individuals with a missense variant on the second allele and two individuals with another frameshift variant on the second allele (Enns et al. 2005; Martín-Hernández et al. 2014; Diez-Fernandez et al. 2017). One of the individuals with two frameshift variants presented with neonatal onset of neurological damage (Martín-Hernández et al. 2014). The other individual with two frameshift variants also presented as a neonate with elevated citrulline levels and hyperammonemia and died aged five days (Diez-Fernandez et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.000016 in the European (non-Finnish) population of the Genome Aggregation Database but this is based on two alleles in a region of good sequence coverage, so the variant is presumed to be rare. Analysis in skin fibroblasts from a patient initially presenting with neurological symptoms post-partum showed undetectable argininosuccinate synthetase activity. A radiolabeled 14C-citrulline/3H-leucine protein incorporation assay confirmed argininosuccinate synthetase deficiency (Enns et al. 2005). Plasma clinical chemistry in this patient show elevated plasma citrulline levels and mild hyperammonemia (Enns et al. 2005). Based on the evidence and the potential impact of frameshift variants, the p.Glu298ArgfsTer18 variant is classified as pathogenic for citrullinemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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

From Baylor Genetics, SCV001163593.1

#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 Natera, Inc., SCV001453091.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Aug 27, 2021

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