Submissions for variant NM_000026.4(ADSL):c.340T>C (p.Tyr114His)

gnomAD frequency: 0.00009  dbSNP: rs374259530

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186703	SCV000240269	pathogenic	not provided	2022-01-24	criteria provided, single submitter	clinical testing	Published functional studies demonstrate pronounced protein instability and significantly reduced or absent enzyme activity (Kmoch et al., 2000; Zikanova et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20127976, 22812634, 16839792, 10888601, 18524658, 29655203, 31467849, 31623504, 22180458, 31589614, 17188615, 33648541)
Genetic Services Laboratory, University of Chicago	RCV000193076	SCV000246325	pathogenic	Adenylosuccinate lyase deficiency	2014-07-16	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415212	SCV000492860	pathogenic	Generalized myoclonic seizure; Progressive neurologic deterioration; Inability to walk; Difficulty standing; Severe global developmental delay	2015-06-22	criteria provided, single submitter	clinical testing
Invitae	RCV000193076	SCV000631367	pathogenic	Adenylosuccinate lyase deficiency	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 114 of the ADSL protein (p.Tyr114His). This variant is present in population databases (rs374259530, gnomAD 0.007%). This missense change has been observed in individual(s) with adenylosuccinate lyase deficiency (PMID: 10888601, 18524658, 20127976). ClinVar contains an entry for this variant (Variation ID: 204807). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ADSL function (PMID: 22180458). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000193076	SCV000894267	pathogenic	Adenylosuccinate lyase deficiency	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000186703	SCV001249556	pathogenic	not provided	2017-02-01	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000193076	SCV002579432	pathogenic	Adenylosuccinate lyase deficiency	2021-08-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002513975	SCV003749139	pathogenic	Inborn genetic diseases	2021-06-17	criteria provided, single submitter	clinical testing	The c.340T>C (p.Y114H) alteration is located in exon 2 (coding exon 2) of the ADSL gene. This alteration results from a T to C substitution at nucleotide position 340, causing the tyrosine (Y) at amino acid position 114 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD), the ADSL c.340T>C alteration was observed in 0.0035% (10/282644) of total alleles studied, with a frequency of 0.007% (9/128972) in the European (non-Finnish) subpopulation. This alteration has been reported in the compound heterozygous state with another ADSL alteration in several unrelated patients with clinical and biochemical features consistent with adenylosuccinase deficiency (Kmoch, 2000; Mouchegh, 2007; Jurecka, 2008; Mastrangelo, 2019). This amino acid position is well conserved in available vertebrate species. In vitro studies have demonstrated protein instability and significantly reduced or absent ADSL activity for the p.Y114H alteration (Kmoch, 2000; Jurecka, 2008; Zikanova, 2010). The p.Y114H alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.