Submissions for variant NM_054012.4(ASS1):c.571G>A (p.Glu191Lys)

gnomAD frequency: 0.00003  dbSNP: rs777828000

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000190357	SCV000796863	likely pathogenic	Citrullinemia type I	2018-01-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000190357	SCV001163229	pathogenic	Citrullinemia type I	2024-03-25	criteria provided, single submitter	clinical testing
Invitae	RCV001376580	SCV001211484	pathogenic	Citrullinemia	2023-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 191 of the ASS1 protein (p.Glu191Lys). This variant is present in population databases (rs777828000, gnomAD 0.01%). This missense change has been observed in individual(s) with citrullinemia (PMID: 12815590, 24713661, 28111830; Invitae). ClinVar contains an entry for this variant (Variation ID: 208153). 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) performed at Invitae indicates that this missense variant is expected to disrupt ASS1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001376580	SCV004804496	pathogenic	Citrullinemia	2024-01-12	criteria provided, single submitter	clinical testing	Variant summary: ASS1 c.571G>A (p.Glu191Lys) results in a conservative amino acid change located in the Arginosuccinate synthase C-terminal domain (IPR048268) 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 2e-05 in 251436 control chromosomes (gnomAD). c.571G>A has been reported in the literature in multiple individuals affected with Citrullinemia Type I (Gao_2003, Sahoo_2015, Diez-Fernandez_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant showed less than 10% of WT activity in transfected cells (Zielonka_2019). The following publications have been ascertained in the context of this evaluation (PMID: 28111830, 12815590, 24713661, 31469252). ClinVar contains an entry for this variant (Variation ID: 208153). Based on the evidence outlined above, the variant was classified as pathogenic.
Molecular Genetics, Royal Melbourne Hospital	RCV000190357	SCV004812359	likely pathogenic	Citrullinemia type I	2023-04-11	criteria provided, single submitter	clinical testing	This sequence change in ASS1 is predicted to replace glutamic acid with lysine at codon 191, p.(Glu191Lys). The glutamic acid residue is highly conserved (84/84 vertebrates, UCSC), and is located in the citrulline/aspartate binding domain (PMID: 12815590). There is a small physicochemical difference between glutamic acid and lysine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.01% (3/24,962 alleles) in the African/African American population, which is consistent with a recessive disease. This variant has been detected in at least ten individuals with citrullinaemia. Of those individuals, seven individuals were homozygous and three were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (PMID: 12815590, 24713661, 28111830, 33190319, 36685561). At least one of these patients displayed a marked elevation in plasma citrulline concentrations, which is highly specific for ASS1 deficiency (PMID: 20301396, 20301631). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.973). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM3_Strong, PP3_Moderate, PM2_Supporting, PP4.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000190357	SCV000153773	pathogenic	Citrullinemia type I	2014-05-25	no assertion criteria provided	clinical testing	Homozygous missense mutation in the ASS1 gene.
Natera, Inc.	RCV000190357	SCV001453086	pathogenic	Citrullinemia type I	2020-09-16	no assertion criteria provided	clinical testing