Submissions for variant NM_054012.4(ASS1):c.323G>T (p.Arg108Leu)

dbSNP: rs35269064

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000436562	SCV000518274	likely benign	not specified	2018-02-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV001273804	SCV000630056	benign	Citrullinemia	2024-01-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000006706	SCV000800762	likely benign	Citrullinemia type I	2017-05-09	criteria provided, single submitter	clinical testing
Mendelics	RCV000006706	SCV001137917	likely benign	Citrullinemia type I	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000006706	SCV001330865	uncertain significance	Citrullinemia type I	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000436562	SCV001361259	likely benign	not specified	2022-02-18	criteria provided, single submitter	clinical testing	Variant summary: ASS1 c.323G>T (p.Arg108Leu) results in a non-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 0.0038 in 394424 control chromosomes, including 11 homozygotes (gnomAD v2.1 and v3.1 non-v2 datasets). The variant was reported predominantly within the African or African-American subpopulation at a frequency of 0.014 (including 7 homozygotes), the observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3.4-fold of the estimated maximal expected allele frequency for a pathogenic variant in ASS1 causing Citrullinemia Type I phenotype (0.0041), strongly suggesting that the variant is a benign polymorphism. Though the variant, c.323G>T, has been reported in the literature in individuals affected with Citrullinemia Type I (Vilaseca_2001, Haberle_2002, Tabor_2014,), these reports do not provide unequivocal conclusions about association of the variant with Citrullinemia Type I. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=2), likely benign (n=3) / benign (n=2). Based on the evidence outlined above, the variant was classified as benign.
Genome-Nilou Lab	RCV000006706	SCV001653418	uncertain significance	Citrullinemia type I	2021-05-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001705583	SCV004156514	benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	ASS1: BS1, BS2
OMIM	RCV000006706	SCV000026897	pathogenic	Citrullinemia type I	2002-04-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001273804	SCV001457305	benign	Citrullinemia	2019-08-02	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001705583	SCV001921481	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000436562	SCV001970670	benign	not specified		no assertion criteria provided	clinical testing