ClinVar Miner

Submissions for variant NM_054012.4(ASS1):c.174+1G>T (rs748264993)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota RCV000761224 SCV000891180 likely pathogenic Citrullinemia type I 2018-09-10 criteria provided, single submitter clinical testing
Baylor Genetics RCV000761224 SCV001163217 pathogenic Citrullinemia type I criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000761224 SCV001369939 likely pathogenic Citrullinemia type I 2019-08-16 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2.
Invitae RCV001376557 SCV001413180 pathogenic Citrullinemia 2019-10-20 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 of the ASS1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs748264993, ExAC 0.01%). Disruption of this splice site has been observed in combination with another ASS1 variant individuals, affected with citrullinemia (PMID: 25179242, 16475226). This variant is also known as IVS4+1G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 623124). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ASS1 are known to be pathogenic (PMID: 18473344, 19006241). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000761224 SCV001471499 likely pathogenic Citrullinemia type I 2019-10-01 criteria provided, single submitter clinical testing The ASS1 c.174+1G>T variant (rs748264993), also known as IVS4 + 1G>T, is reported in the literature in an individual with citrullinemia who carried an additional pathogenic variant presumably in trans (Kleijer 2006). A different variant at this nucleotide (c.174+1G>A) is also reported in association with citrullinemia, and shown to cause exon skipping which is predicted to alter the ATP binding domain of the protein (Karlberg 2008, Kimani 2015). The c.174+1G>T variant is reported in ClinVar (Variation ID: 623124). It is only observed in 2 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron 4, which is likely to negatively impact gene function. Based on available information, this variant is considered to be likely pathogenic. REFERENCES Karlberg T et al. Structure of human argininosuccinate synthetase. Acta Crystallogr D Biol Crystallogr. 2008 Mar;64(Pt 3):279-86. Kimani JK et al. Functional analysis of novel splicing and missense mutations identified in the ASS1 gene in classical citrullinemia patients. Clin Chim Acta. 2015 Jan 1;438:323-9. Kleijer WJ et al. Prenatal diagnosis of citrullinemia and argininosuccinic aciduria: evidence for a transmission ratio distortion in citrullinemia. Prenat Diagn. 2006 Mar;26(3):242-7.

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