Submissions for variant NM_001032386.2(SUOX):c.1097G>A (p.Arg366His)

gnomAD frequency: 0.00001  dbSNP: rs776690106

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268179	SCV001446905	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002290677	SCV002581873	likely pathogenic	Sulfite oxidase deficiency	2022-08-22	criteria provided, single submitter	clinical testing
Invitae	RCV002290677	SCV003264864	pathogenic	Sulfite oxidase deficiency	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 366 of the SUOX protein (p.Arg366His). This variant is present in population databases (rs776690106, gnomAD 0.01%). This missense change has been observed in individual(s) with dystonia and/or sulfite oxidase deficiency (PMID: 12112661, 33098801, 34741542, 35872528). This variant is also known as R309H. ClinVar contains an entry for this variant (Variation ID: 986985). 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 SUOX protein function with a positive predictive value of 80%. This variant disrupts the p.Arg366 amino acid residue in SUOX. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31870341). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV002290677	SCV004238376	pathogenic	Sulfite oxidase deficiency	2023-11-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003492239	SCV004241047	pathogenic	Sulfocysteinuria	2023-12-13	criteria provided, single submitter	clinical testing	Variant summary: SUOX c.1097G>A (p.Arg366His) results in a non-conservative amino acid change located in the oxidoreductase, molybdopterin-binding domain (IPR000572) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251452 control chromosomes (gnomAD). c.1097G>A has been reported in the literature as a biallelic genotype in individuals affected with and/or with clinical features of (ie. generalized dystonia, ataxia, developmental delay, seizures) Sulfite Oxidase Deficiency (e.g. Johnson_2002, Zech_2020, Kaczmarek_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The variant demonstrated compromised Moco binding and the most pronounced effect results in <10% of WT activity when overexpressed in HEK SUOX-/- cells (Kaczmarek_2021). The following publications have been ascertained in the context of this evaluation (PMID: 35872528, 12112661, 34741542, 33098801). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.