Submissions for variant NM_000263.4(NAGLU):c.1834A>G (p.Ser612Gly)

gnomAD frequency: 0.00013  dbSNP: rs148881970

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Undiagnosed Diseases Network, NIH	RCV000625994	SCV000746600	pathogenic	Mucopolysaccharidosis, MPS-III-B	2017-02-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000686454	SCV000813973	pathogenic	Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 612 of the NAGLU protein (p.Ser612Gly). This variant is present in population databases (rs148881970, gnomAD 0.01%). This missense change has been observed in individual(s) with a mild form of mucopolysaccharidosis type IIIB (PMID: 9443875, 20852935, 21712855, 25256447, 26907177). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 522823). 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 NAGLU protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects NAGLU function (PMID: 21712855). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000686454	SCV000894120	pathogenic	Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V	2021-10-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000625994	SCV000914767	pathogenic	Mucopolysaccharidosis, MPS-III-B	2018-11-01	criteria provided, single submitter	clinical testing	The NAGLU c.1834A>G (p.Ser612Gly) variant has been reported in four studies and in a total of 11 probands with mucopolysaccharidosis including ten probands in a compound heterozygous state and one proband in a homozygous state (Zhao et al. 1998; Verhoeven et al. 2010; Valstar et al. 2010; Selmer et al. 2012). Segregation analysis confirmed co-segregation with disease in a clear autosomal recessive inheritance pattern in two families (Zhao et al. 1998; Selmer et al. 2012). Control data are unavailable for this variant, which is reported at a frequency of 0.00022 in the European (non-Finnish) population of the Exome Aggregation Consortium. Two studies demonstrated deficient alpha-N-acetyl glucosaminidase (NAGLU) enzyme activity in cultured fibroblasts from affected subjects (Verhoeven et al. 2010; Selmer et al. 2012). In five of the six families reported, this variant was associated with an attenuated phenotype of MPS IIIB with a slower progression of disease. Based on the collective evidence the p.Ser612Gly variant is classified as a pathogenic variant for mucopolysaccharidosis type III. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268050	SCV001446654	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV001268050	SCV001448901	pathogenic	not provided	2019-12-13	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001268050	SCV002018199	pathogenic	not provided	2021-02-05	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000625994	SCV002102467	pathogenic	Mucopolysaccharidosis, MPS-III-B	2022-02-25	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous with NM_000263.4:c.219_237del._x000D_ Criteria applied: PM3_VSTR, PP4_STR, PP3
GeneDx	RCV001268050	SCV004168103	pathogenic	not provided	2023-04-21	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect, as the variant results in loss of enzyme activity (Clark et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29979746, 28751108, 20852935, 9443875, 35848209, 31718697, 34347683, 25256447, 21712855, 20040070, 31980526, 26907177)
GeneReviews	RCV001030809	SCV001194298	not provided	Mucopolysaccharidosis		no assertion provided	literature only
Natera, Inc.	RCV000625994	SCV001463392	pathogenic	Mucopolysaccharidosis, MPS-III-B	2020-09-16	no assertion criteria provided	clinical testing