ClinVar Miner

Submissions for variant NM_054012.4(ASS1):c.929A>G (p.Lys310Arg) (rs199751308)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,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 2020-05-15 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 310 of the ASS1 protein (p.Lys310Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs199751308, ExAC 0.001%). This variant has been reported in combination with other ASS1 variants in individuals affected with mild argininosuccinate synthetase deficiency or citrullinemia type I (PMID: 15863597, Invitae). In addition, this variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with citrullinemia type I (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 365260). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000286574 SCV001163596 likely pathogenic Citrullinemia type I criteria provided, single submitter clinical testing

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