Submissions for variant NM_054012.4(ASS1):c.929A>G (p.Lys310Arg)

gnomAD frequency: 0.00002  dbSNP: rs199751308

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000286574	SCV000477633	uncertain significance	Citrullinemia type I	2018-05-04	criteria provided, single submitter	clinical testing	The ASS1 c.929A>G (p.Lys310Arg) variant is a missense variant that has been reported in a compound heterozygous state in at least one individual with citrullinemia type I (Enns et al. 2005; Gao et al. 2003). Control data are unavailable for this variant, which is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project. This frequency is based on only one allele in a region of good sequencing coverage, so the variant is presumed to be rare. The evidence for this variant is limited. The p.Lys310Arg variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for citrullinemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx	RCV000413247	SCV000491197	likely pathogenic	not provided	2016-08-31	criteria provided, single submitter	clinical testing	The K310R variant in the ASS1 gene has been reported in a patient with adult/late-onset classic citrullinemia who had no detectable arginosuccinate synthetase activity in fibroblasts and who also harbored a pathogenic frameshift variant in the ASS1 gene (Gao et al. 2003). The K310R variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This substitution occurs at a position that is conserved across species. Furthermore, K310 is located within the catalytic domain of the argininosuccinate synthetase enzyme and is believed to be involved with dimer interaction, and another missense variant at the same position (K310Q) has been identified in a patient with no detectable argininosuccinate synthetase activity who also harbored a splice site variant in the ASS1 gene (Gao et al. 2003). In summary, we interpret K310R to be likely pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506573	SCV000602548	likely pathogenic	not specified	2017-03-21	criteria provided, single submitter	clinical testing
Invitae	RCV001376638	SCV000754764	pathogenic	Citrullinemia	2023-06-05	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Lys310 amino acid residue in ASS1. Other variant(s) that disrupt this residue have been observed in individuals with ASS1-related conditions (PMID: 15266621), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ASS1 protein function. ClinVar contains an entry for this variant (Variation ID: 365260). This missense change has been observed in individual(s) with clinical features of ASS1-related conditions (PMID: 12815590, 15863597; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs199751308, gnomAD 0.004%). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 310 of the ASS1 protein (p.Lys310Arg).
Baylor Genetics	RCV000286574	SCV001163596	likely pathogenic	Citrullinemia type I		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000286574	SCV002024392	likely pathogenic	Citrullinemia type I	2019-06-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000506573	SCV003922700	uncertain significance	not specified	2023-03-09	criteria provided, single submitter	clinical testing	Variant summary: ASS1 c.929A>G (p.Lys310Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251470 control chromosomes (gnomAD). c.929A>G has been reported in the literature in at-least one individual affected with Citrullinemia Type I (example: Gao_2003 and Enns_2005). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant affecting this residue (c.928A>C p.K310Q) have been reported in an individual affected with Citrullinemia (Gao_2003), suggesting this residue may be critical for normal protein function. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and pathogenic/likely pathogenic (n=4). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.