ClinVar Miner

Submissions for variant NM_054012.4(ASS1):c.256C>T (p.Arg86Cys) (rs121908644)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001376621 SCV000630054 pathogenic Citrullinemia 2020-10-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 86 of the ASS1 protein (p.Arg86Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs121908644, ExAC 0.03%). This variant has been reported as homozygous in individuals affected with citrullinemia type 1 (PMID: 25433810). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with citrullinemia type 1 (PMID: 1943692). 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: 6332). An experimental study has shown that skin fibroblasts derived from an individual that carried this variant in combination with another deleterious ASS1 variant present no detectable ASS1 enzymatic activity, indicating that p.Arg86Cys abrogates ASS1 protein function (PMID: 1943692). A different missense substitution at this codon (p.Arg86His) has been determined to be pathogenic (PMID: 12815590, 12815590). This suggests that the arginine residue is critical for ASS1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000006704 SCV001163218 pathogenic Citrullinemia type I criteria provided, single submitter clinical testing
GeneDx RCV001555941 SCV001777435 pathogenic not provided 2019-04-24 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31469252, 12815590, 28111830, 7977368, 24508627, 24772957, 19006241, 25433810, 1943692, 22494545)
OMIM RCV000006704 SCV000026895 pathogenic Citrullinemia type I 1991-02-01 no assertion criteria provided literature only
Counsyl RCV000006704 SCV000792452 likely pathogenic Citrullinemia type I 2017-06-27 no assertion criteria provided clinical testing

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