ClinVar Miner

Submissions for variant NM_054012.4(ASS1):c.970G>A (p.Gly324Ser)

gnomAD frequency: 0.00003  dbSNP: rs121908639
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000006699 SCV000220532 likely pathogenic Citrullinemia type I 2014-07-19 criteria provided, single submitter literature only
Genetic Services Laboratory, University of Chicago RCV000006699 SCV000593461 likely pathogenic Citrullinemia type I 2016-01-17 criteria provided, single submitter clinical testing
Invitae RCV001376631 SCV000630068 pathogenic Citrullinemia 2024-01-16 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 324 of the ASS1 protein (p.Gly324Ser). This variant also falls at the last nucleotide of exon 13, which is part of the consensus splice site for this exon. This variant is present in population databases (rs121908639, gnomAD 0.01%). This missense change has been observed in individual(s) with citrullinemia (PMID: 2358466, 11211875, 12815590, 14680976, 18473344). ClinVar contains an entry for this variant (Variation ID: 6327). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000006699 SCV001163598 pathogenic Citrullinemia type I criteria provided, single submitter clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000006699 SCV001368808 pathogenic Citrullinemia type I 2019-01-31 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3,PP3,PP4.
CeGaT Center for Human Genetics Tuebingen RCV001531743 SCV001747007 pathogenic not provided 2021-07-01 criteria provided, single submitter clinical testing
3billion RCV000006699 SCV002012159 pathogenic Citrullinemia type I 2021-10-02 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000006327.8, PS1). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000358, PM2). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID:16475226, 12815590 PM3). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97, 3Cnet: 0.990, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001376631 SCV002572032 pathogenic Citrullinemia 2022-08-01 criteria provided, single submitter clinical testing Variant summary: ASS1 c.970G>A (p.Gly324Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251184 control chromosomes. c.970G>A has been reported in the literature in numerous individuals affected with Citrullinemia Type I, in the homozygous and compound heterozygous state (examples: Gao_2003, Haberle_2003, Lee_2013, etc). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000006699 SCV002787433 pathogenic Citrullinemia type I 2022-04-18 criteria provided, single submitter clinical testing
Centre de Genetique Humaine, Institut de Pathologie et de Genetique RCV000006699 SCV004190118 pathogenic Citrullinemia type I 2023-12-21 criteria provided, single submitter clinical testing The c.970G>A impacts a highly conserved nucleotide (phyloP: 9.18) and a highly conserved amino acid (down to the yeast). It has 2 occurrences in gnomAD v4. Prediction tools pedict a deleterious effect (20/21), CADD : 34, REVEL 0.970. It is predicted to alter splicing (SpliceAI : donor loss 0.67). In vitro data revealed complete loss of enzyme activity (residual activity <2%) (PMID: 18473344). Despite having a severe impact on enzyme activity in vitro, the variant was reported in two asymptomatic patients with citrullinemia type 1, one was hmozygote for the variant and the second was compound heterozygote with the c.40G>A p.(Gly14Ser) variant (PMID: 14680976). It was also reported in a Korean cohort with neonatal onset (1 to 16d, in trans with c.421-2A>G) or later onset (3m, in trans with c.421-2A>G or c.1128-6_1188dup67) (PMID: 23246278). Our patient (mild form of ASSD) carries the c.808G>C variant in cis with c.206T>C, inherited from his father, and in trans with c.970G>A, inherited from his mother. Intriguingly, the paternal allele of our patient is composed of the two variants reported in PMID: 11708871, which are presumably in trans in the published patient (severe case). There is second published patient who also carries the same two variants with no reported segregation (PMID: 12815590). In gnomAD, c.206T>C and c.808G>C have the same number of occurrences (v2.1.1 : 2-2, v4.0.0 : 5-5). These two variant might be on the same haplotype and we postulate that there is a third variant in trans that was not found in the first published case (PMID: 11708871). This would explain why our patient has a mild phenotype resulting from an hypomorphic allele c.970G>A (PMID: 14680976) + a severe allele [c.206T>C;c.808G>C].
OMIM RCV000006699 SCV000026890 pathogenic Citrullinemia type I 2013-04-04 no assertion criteria provided literature only
Natera, Inc. RCV000006699 SCV002085106 pathogenic Citrullinemia type I 2021-01-20 no assertion criteria provided clinical testing

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