Submissions for variant NM_054012.4(ASS1):c.174+4C>A

gnomAD frequency: 0.00016  dbSNP: rs368133957

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000343497	SCV000477617	uncertain significance	Citrullinemia type I	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000616413	SCV000727967	likely benign	not specified	2018-03-01	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002523738	SCV003255701	uncertain significance	Citrullinemia	2022-08-31	criteria provided, single submitter	clinical testing	This sequence change falls in intron 4 of the ASS1 gene. It does not directly change the encoded amino acid sequence of the ASS1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs368133957, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with ASS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 365250). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.
Ambry Genetics	RCV002523739	SCV003553760	uncertain significance	Inborn genetic diseases	2022-05-04	criteria provided, single submitter	clinical testing	The c.174+4C>A intronic alteration consists of a C to A substitution 4 nucleotides after exon 4 (coding exon 2) of the ASS1 gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV000343497	SCV001453075	likely benign	Citrullinemia type I	2020-09-16	no assertion criteria provided	clinical testing