Submissions for variant NM_054012.4(ASS1):c.1128-6_1188dup

dbSNP: rs1554725677

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590599	SCV000694160	pathogenic	Citrullinemia type I	2016-02-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001376617	SCV001419957	pathogenic	Citrullinemia	2021-08-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 495381). This variant is also known as 1127_1128ins67. This premature translational stop signal has been observed in individuals with citrullinemia type I (PMID: 12815590, 23099195, 23246278). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg398Glnfs*7) in the ASS1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 15 amino acid(s) of the ASS1 protein.
3billion	RCV000590599	SCV002012160	pathogenic	Citrullinemia type I	2021-10-02	criteria provided, single submitter	clinical testing	Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000495381.3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001376617	SCV003928980	pathogenic	Citrullinemia	2023-04-25	criteria provided, single submitter	clinical testing	Variant summary: ASS1 c.1128-6_1188dup67 (p.Arg398Glnfs*7) is expected to create a premature stop codon resulting in a truncated or absent protein. The variant was absent in 249548 control chromosomes. c.1128-6_1188dup67 has been reported in the literature in multiple individuals affected with Citrullinemia Type I (Lee_2013, Woo_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23246278, 23099195). Two 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. Based on the evidence outlined above, the variant was classified as pathogenic.