ClinVar Miner

Submissions for variant NM_000048.4(ASL):c.299T>C (p.Ile100Thr) (rs202142867)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587929 SCV000694150 pathogenic Argininosuccinate lyase deficiency 2016-09-09 criteria provided, single submitter clinical testing Variant summary: The c.299T>C (p.Ile100Thr) in ASL gene is a missense change that alters a highly conserved nucleotide and 4/5 in silico tools predict deleterious outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.00014 (17/118940 chrs tested). This frequency does not exceed the maximal expected allele frequency for a pathogenic variant in ASL gene (0.004). The results of functional studies are contradictious, depending on the expression system and ranging from ~90% of residual enzymatic activity in HEK293T to no detectable activity in bacterial cells. Since there is no information from the most reliable functional assay, such as citrulline incorporation was published at the time of evaluation, the results from the other functional assays mentioned above should be taken with caution. The variant was found homozygously or in compound heterozygosity in multiple affected individuals with established diagnosis of ASLD. Taken together, the variant was classified as Pathogenic.
Counsyl RCV000587929 SCV000789572 likely pathogenic Argininosuccinate lyase deficiency 2017-02-13 criteria provided, single submitter clinical testing
Invitae RCV000587929 SCV000819747 likely pathogenic Argininosuccinate lyase deficiency 2020-10-13 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 100 of the ASL protein (p.Ile100Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs202142867, ExAC 0.2%). This variant has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 12384776, 18616627, 22231378). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 495379). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ASL protein function (PMID: 21667091, 25778938, 31943503). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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