ClinVar Miner

Submissions for variant NM_054012.4(ASS1):c.805G>A (p.Val269Met)

gnomAD frequency: 0.00007  dbSNP: rs370595480
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000412912 SCV000490413 likely pathogenic not provided 2023-03-30 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30285816, 25087612, 23891399, 28132756, 12815590, 14680976, 31469252, 12684898, 32778825, 33851512, 35281663)
Genetic Services Laboratory, University of Chicago RCV000174211 SCV000593462 likely pathogenic Citrullinemia type I 2017-04-13 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001290023 SCV000957991 pathogenic Citrullinemia 2024-01-17 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 269 of the ASS1 protein (p.Val269Met). This variant is present in population databases (rs370595480, gnomAD 0.01%). This missense change has been observed in individual(s) with mild citrullinemia type 1 (PMID: 12815590, 14680976; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 193968). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ASS1 protein function. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000174211 SCV001163590 pathogenic Citrullinemia type I 2024-03-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001290023 SCV002555957 likely pathogenic Citrullinemia 2022-06-02 criteria provided, single submitter clinical testing Variant summary: ASS1 c.805G>A (p.Val269Met) 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 5.2e-05 in 251314 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ASS1 causing Citrullinemia Type I (5.2e-05 vs 0.0041), allowing no conclusion about variant significance. c.805G>A has been reported in the literature in individuals affected with citrullinemia or urea cycle disorders. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating protein residual activity, however, does not allow convincing conclusions about the variant effect (Zielonka_2019). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Pathogenic n=1, likely pathogenic n=2, VUS n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000174211 SCV005674844 likely pathogenic Citrullinemia type I 2024-01-04 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000412912 SCV000225474 uncertain significance not provided 2018-06-22 flagged submission clinical testing
Counsyl RCV000174211 SCV000800723 uncertain significance Citrullinemia type I 2017-04-18 flagged submission clinical testing

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