ClinVar Miner

Submissions for variant NM_000048.4(ASL):c.209T>C (p.Val70Ala)

gnomAD frequency: 0.00001  dbSNP: rs1027739421
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665127 SCV000789193 uncertain significance Argininosuccinate lyase deficiency 2018-02-02 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000665127 SCV003284014 uncertain significance Argininosuccinate lyase deficiency 2022-08-15 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 70 of the ASL protein (p.Val70Ala). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with argininosuccinate lyase deficiency (PMID: 24166829). ClinVar contains an entry for this variant (Variation ID: 550394). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004782497 SCV005394575 uncertain significance not specified 2024-09-12 criteria provided, single submitter clinical testing Variant summary: ASL c.209T>C (p.Val70Ala) results in a non-conservative amino acid change located in the fumarate lyase, N-terminal domain (IPR022761) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 244992 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.209T>C has been reported in the literature in at least an individual affected with argininosuccinic aciduria (example: Balmer_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Argininosuccinic Aciduria. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 24166829). ClinVar contains an entry for this variant (Variation ID: 550394). Based on the evidence outlined above, the variant was classified as uncertain significance.

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