Submissions for variant NM_000199.5(SGSH):c.364G>A (p.Gly122Arg)

gnomAD frequency: 0.00002  dbSNP: rs761607612

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000612947	SCV000745251	pathogenic	Mucopolysaccharidosis, MPS-III-A	2015-09-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000612947	SCV000797367	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2018-01-24	criteria provided, single submitter	clinical testing
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	RCV000612947	SCV000929894	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2019-01-01	criteria provided, single submitter	literature only	PS3: Low in vitro enzymatic activity. PM2: Very low frequency in ExAc
Invitae	RCV000612947	SCV000954450	pathogenic	Mucopolysaccharidosis, MPS-III-A	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 122 of the SGSH protein (p.Gly122Arg). This variant is present in population databases (rs761607612, gnomAD 0.01%). This missense change has been observed in individuals with mucopolysaccharidosis (PMID: 9401012, 9554748, 11182930, 21061399, 22976768, 27590925; Invitae). ClinVar contains an entry for this variant (Variation ID: 518269). 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 SGSH protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SGSH function (PMID: 10727844). This variant disrupts the p.Arg122 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been observed in individuals with SGSH-related conditions (PMID: 24875751), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV000612947	SCV001548178	pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-03-25	criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814197	SCV001755594	pathogenic	Abnormality of metabolism/homeostasis	2021-07-10	criteria provided, single submitter	clinical testing
GeneDx	RCV001539080	SCV001756817	pathogenic	not provided	2021-08-05	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on enzyme activity (Esposito et al., 2000); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 9401012, 9554748, 11182930, 11668611, 21204211, 22002444, 24875751, 30809705, 10727844, 22976768, 27590925, 21061399, 25557439, 25807448, 24816101)
Genome-Nilou Lab	RCV000612947	SCV002045505	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-11-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000612947	SCV004201116	pathogenic	Mucopolysaccharidosis, MPS-III-A	2023-06-15	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000612947	SCV000733743	pathogenic	Mucopolysaccharidosis, MPS-III-A		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000612947	SCV002095144	pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-02-22	no assertion criteria provided	clinical testing