ClinVar Miner

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

gnomAD frequency: 0.00003  dbSNP: rs777828000
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Total submissions: 7
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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 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

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