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

gnomAD frequency: 0.00004  dbSNP: rs770362721

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169181	SCV000220418	likely pathogenic	Citrullinemia type I	2014-06-16	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169181	SCV000694166	pathogenic	Citrullinemia type I	2016-05-04	criteria provided, single submitter	clinical testing	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.
Invitae	RCV001376598	SCV000818931	pathogenic	Citrullinemia	2022-10-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu298Argfs*18) in the ASS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ASS1 are known to be pathogenic (PMID: 18473344, 19006241). This variant is present in population databases (rs770362721, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with citrullinemia type I (PMID: 15863597, 25433810). ClinVar contains an entry for this variant (Variation ID: 188832). 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.
Illumina Laboratory Services, Illumina	RCV000169181	SCV000915271	pathogenic	Citrullinemia type I	2017-09-18	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000169181	SCV001163593	pathogenic	Citrullinemia type I		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000169181	SCV002019932	pathogenic	Citrullinemia type I	2021-08-18	criteria provided, single submitter	clinical testing
GeneDx	RCV002225489	SCV002504156	pathogenic	not provided	2022-04-07	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate the variant results in reduced enzyme activity (Zielonka et al., 2019); This variant is associated with the following publications: (PMID: 24508627, 31469252, 15863597, 12815590, 19006241, 25433810)
CeGaT Center for Human Genetics Tuebingen	RCV002225489	SCV004010876	pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing	ASS1: PVS1, PM2, PM3, PP4:Moderate
Natera, Inc.	RCV000169181	SCV001453091	pathogenic	Citrullinemia type I	2020-09-16	no assertion criteria provided	clinical testing