Submissions for variant NM_000026.4(ADSL):c.5C>T (p.Ala2Val)

dbSNP: rs143083947

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186704	SCV000240270	pathogenic	not provided	2012-04-09	criteria provided, single submitter	clinical testing	p.Ala2Val (GCG>GTG): c.5 C>T in exon 1 of the ADSL gene. The Ala2Val mutation has been reported previously, together with mutation Ser395Arg, in a patient with neonatal myoclonic seizures, developmental delay, and hypotonia due to adenylosuccinate lyase (ADSL) deficiency (Marie et al., 1999; van den Bergh et al., 1998). The Ala2Val mutation alters a highly conserved position in the ADSL protein, and in vitro functional studies indicate that this mutation reduces ADSL enzyme activity (Race et al., 2000). The variant is found in INFANT-EPI panel(s).
Invitae	RCV001363283	SCV001559389	uncertain significance	Adenylosuccinate lyase deficiency	2022-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2 of the ADSL protein (p.Ala2Val). This variant is present in population databases (rs143083947, gnomAD 0.1%). This missense change has been observed in individual(s) with adenylosuccinate lyase deficiency (PMID: 10090474). ClinVar contains an entry for this variant (Variation ID: 204808). 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 not expected to disrupt ADSL protein function. 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.
3billion	RCV001363283	SCV004013580	uncertain significance	Adenylosuccinate lyase deficiency		criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.012%). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with ADSL related disorder (ClinVar ID: VCV000204808 / PMID: 10090474). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 10958654). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as Uncertain significance according to the recommendation of ACMG/AMP guideline.