Submissions for variant NM_000026.4(ADSL):c.1342T>C (p.Ser448Pro)

gnomAD frequency: 0.00001  dbSNP: rs771121666

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224729	SCV000280981	likely pathogenic	not provided	2016-05-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526230	SCV000631363	pathogenic	Adenylosuccinate lyase deficiency	2025-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 448 of the ADSL protein (p.Ser448Pro). This variant is present in population databases (rs771121666, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of ADSL-related conditions ‚Äã (PMID: 16839792, 24781210; internal data). ClinVar contains an entry for this variant (Variation ID: 235410). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ADSL protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000224729	SCV000779631	pathogenic	not provided	2024-09-16	criteria provided, single submitter	clinical testing	Biochemical testing in one of the previously reported individuals revealed elevated succinyladenosine urinary excretion, confirming dysfunction of adenylosuccinate lyase (ADSL) (PMID: 24781210); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24781210, 16839792)
Baylor Genetics	RCV000526230	SCV001529349	likely pathogenic	Adenylosuccinate lyase deficiency	2018-07-12	criteria provided, single submitter	clinical testing	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in two unrelated patients with ADSL deficiency in compound heterozygous with other variants [PMID 16839792, 24781210]
Ambry Genetics	RCV002516223	SCV003551929	uncertain significance	Inborn genetic diseases	2022-06-16	criteria provided, single submitter	clinical testing	The c.1342T>C (p.S448P) alteration is located in exon 12 (coding exon 12) of the ADSL gene. This alteration results from a T to C substitution at nucleotide position 1342, causing the serine (S) at amino acid position 448 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000526230	SCV004039025	likely pathogenic	Adenylosuccinate lyase deficiency	2023-08-11	criteria provided, single submitter	clinical testing	Variant summary: ADSL c.1342T>C (p.Ser448Pro) results in a non-conservative amino acid change located in the Adenylosuccinate lyase C-terminal (IPR019468) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251482 control chromosomes (gnomAD). c.1342T>C has been reported in the literature in individuals affected with Adenylosuccinate Lyase Deficiency (Spiegel_2006, Michael_2014), and one was compound heterozygous with a variant that has been classified as pathogenic by a ClinVar submitter. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16839792, 24781210). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic (n=2), likely pathogenic (n=2), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.