Submissions for variant NM_000026.4(ADSL):c.1337C>A (p.Pro446His)

gnomAD frequency: 0.00001  dbSNP: rs755964863

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000726681	SCV000619985	uncertain significance	not provided	2017-08-15	criteria provided, single submitter	clinical testing	The P446H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P446H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P446H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (S447P, S448P, t450S) have been reported in the Human Gene Mutation Database in association with ADSL deficiency (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Eurofins Ntd Llc (ga)	RCV000726681	SCV000702089	uncertain significance	not provided	2016-09-26	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000785042	SCV000923595	uncertain significance	Adenylosuccinate lyase deficiency	2019-01-01	criteria provided, single submitter	clinical testing
Invitae	RCV000785042	SCV001205346	uncertain significance	Adenylosuccinate lyase deficiency	2022-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 446 of the ADSL protein (p.Pro446His). This variant is present in population databases (rs755964863, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ADSL-related conditions. ClinVar contains an entry for this variant (Variation ID: 451308). 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 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.