Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Molecular Diagnostics Laboratory, |
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, |
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 | 2023-10-27 | 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. Variants that disrupt the donor or acceptor splice site 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). This variant is present in population databases (rs748264993, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with citrullinemia (PMID: 16475226, 25179242). This variant is also known as IVS4+1G>T. ClinVar contains an entry for this variant (Variation ID: 623124). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
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. |