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

gnomAD frequency: 0.00007  dbSNP: rs370595480

Total submissions: 7

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
Invitae	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.
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