Submissions for variant NM_054012.4(ASS1):c.206T>C (p.Val69Ala)

gnomAD frequency: 0.00001  dbSNP: rs771594651

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, University Hospital Muenster	RCV004584444	SCV002054111	likely pathogenic	See cases	2021-12-04	criteria provided, single submitter	clinical testing	ACMG categories: PM2,PM3,PP3,PP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV002221689	SCV003441493	uncertain significance	Citrullinemia	2022-07-22	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 69 of the ASS1 protein (p.Val69Ala). This variant is present in population databases (rs771594651, gnomAD 0.003%). This missense change has been observed in individual(s) with citrullinemia type I (PMID: 11708871, 12815590). ClinVar contains an entry for this variant (Variation ID: 1332900). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Centre de Genetique Humaine, Institut de Pathologie et de Genetique	RCV003475100	SCV004190116	likely pathogenic	Citrullinemia type I	2023-12-21	criteria provided, single submitter	clinical testing	The c.206T>C p.(Val69Ala) impacts a moderately conserved nucleotide (phyloP: 6.90) and a highly conserved amino acid (down to the yeast). It has 5 occurrences in gnomAD v4. Prediction tools pedict a deleterious effect (16/21), CADD : 25.5, REVEL 0.901. It was reported once in a child who died in the context of hyperammonemia (600µM) after 1 week of life. In this reported child, the second reported variant was p.(Glu270Gln) and the ASS1 enzyme activity was abolished in fibroblasts and in liver tissue (PMID: 11708871). The familial segregation confirming the bi-allelic occurence was not reported in the manuscript. 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].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002221689	SCV005039721	likely pathogenic	Citrullinemia	2024-03-19	criteria provided, single submitter	clinical testing	Variant summary: ASS1 c.206T>C (p.Val69Ala) results in a non-conservative amino acid change located in the Arginosuccinate synthase-like, N-terminal domain (IPR048267) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251046 control chromosomes. c.206T>C has been reported in the literature in homozygous and compound heterozygous individuals affected with Citrullinemia Type I (e.g. Martin-Hernandez_2014, Vilaseca_2001, Zielonka_2019). These data indicate that the variant is likely be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, showing reduced enzyme activity in an affected compound heterozygous patient with a second allele with null activity (e.g. Zielonka_2019, Diez-Hernandez_2016). The following publications have been ascertained in the context of this evaluation (PMID: 25433810, 11708871, 31469252, 27287393). ClinVar contains an entry for this variant (Variation ID: 1332900). Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV004699478	SCV005201868	uncertain significance	not provided	2023-06-15	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: 31469252, 11708871)