Submissions for variant NM_000048.4(ASL):c.1045_1057del (p.Val349fs)

dbSNP: rs796051933

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185780	SCV000238713	pathogenic	not provided	2022-03-21	criteria provided, single submitter	clinical testing	Gel-based analysis of mRNA derived from patient fibroblast cells harboring c.1045_1057del found that this variant frequently results in exon skipping (Barbosa et al. 1991); Frameshift variant predicted to result in protein truncation, as the last 116 amino acids are replaced with 71 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9045711, 21710918, 31943503, 1705937)
Counsyl	RCV000668476	SCV000793086	pathogenic	Argininosuccinate lyase deficiency	2017-08-01	criteria provided, single submitter	clinical testing
Invitae	RCV000668476	SCV000933200	pathogenic	Argininosuccinate lyase deficiency	2023-11-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val349Cysfs*72) in the ASL gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs762010471, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with argininosuccinate lyase deficiency (PMID: 1705937, 16941645, 24166829). ClinVar contains an entry for this variant (Variation ID: 203629). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects ASL function (PMID: 31943503). Studies have shown that this premature translational stop signal results in skipping of exon 14 (also known as exon 13), but is expected to preserve the integrity of the reading-frame (PMID: 16941645). For these reasons, this variant has been classified as Pathogenic.
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV001375026	SCV001572314	pathogenic	Neurodevelopmental disorder	2023-03-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000668476	SCV001737746	pathogenic	Argininosuccinate lyase deficiency	2021-06-16	criteria provided, single submitter	clinical testing	Variant summary: ASL c.1045_1057del13 (p.Val349CysfsX72) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.6e-05 in 250612 control chromosomes (gnomAD). c.1045_1057del13 has been reported in the literature in multiple individuals affected with Argininosuccinic Aciduria (Barbosa_1991, Walker_1997, Beck_2011, Balmer_2014, Zielonka_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports this deletion apparently causes exon skipping (Barbosa_1991). Four submitters (evaluation after 2014) cite the variant as pathogenic (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000668476	SCV004183478	pathogenic	Argininosuccinate lyase deficiency	2023-09-09	criteria provided, single submitter	clinical testing