Submissions for variant NM_000263.4(NAGLU):c.1834A>G (p.Ser612Gly) (rs148881970)

Total submissions: 4

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
Invitae	RCV000686454	SCV000813973	pathogenic	Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease, axonal type 2V	2018-09-11	criteria provided, single submitter	clinical testing	This sequence change replaces serine with glycine at codon 612 of the NAGLU protein (p.Ser612Gly). The serine residue is moderately conserved and there is a small physicochemical difference between serine and glycine. This variant is present in population databases (rs148881970, ExAC 0.02%). This variant has been reported in individuals affected with a mild form of mucopolysaccharidosis type IIIB (PMID: 9443875, 20852935, 217121855, 25256447, 26907177). Experimental studies have shown that cells derived from an individual with this variant and a second missense variant in trans had very low residual NAGLU enzyme activity (PMID: 21712855). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics	RCV000686454	SCV000894120	likely pathogenic	Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease, axonal type 2V	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,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.