ClinVar Miner

Submissions for variant NM_000263.4(NAGLU):c.1900G>A (p.Glu634Lys) (rs147036053)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000779220 SCV000915763 uncertain significance Mucopolysaccharidosis, MPS-III-B 2018-12-07 criteria provided, single submitter clinical testing The NAGLU c.1900G>A (p.Glu634Lys) missense variant has been reported in two studies and found in three individuals with MPS type IIIB from two unrelated families, all in a compound heterozygous state (Valstar et al. 2010; Truxal et al. 2016). In the sibling pair, this variant was associated with an attenuated phenotype of MPS IIIB with a slower progression of disease (Valstar et al. 2010). Control data are unavailable for this variant, which is reported at a frequency of 0.000033 in the European (non-Finnish) population of the Genome Aggregation Database. Though functional studies were not available, one study demonstrated deficient alpha-N-acetyl glucosaminidase (NAGLU) enzyme activity in cultured fibroblasts from the affected sibling pair (Meijer et al. 2016). Based on the limited evidence, the p.Glu634Lys variant is classified as a variant of unknown significance but suspicious for pathogenicity for mucopolysaccharidosis type III. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000806351 SCV000946343 pathogenic Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease, axonal type 2V 2019-02-28 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 634 of the NAGLU protein (p.Glu634Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another NAGLU variant in individuals affected with mucopolysaccharidosis type III (PMID: 20852935, 27590925, Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000779220 SCV001370733 pathogenic Mucopolysaccharidosis, MPS-III-B 2020-05-22 criteria provided, single submitter clinical testing Variant summary: NAGLU c.1900G>A (p.Glu634Lys) results in a conservative amino acid change located in the Alpha-N-acetylglucosaminidase, C-terminal domain (IPR024732) 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 1.3e-05 in 232618 control chromosomes. c.1900G>A has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B, examples: Valstar_2010, Truxal_2016, Whitley_2018). 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 most pronounced variant effect results in 10%-<30% of normal activity (Clark_2018). Three ClinVar submitters (evaluation after 2014) cited the variant as pathogenic (n=2) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneReviews RCV001030810 SCV001194299 pathogenic Mucopolysaccharidosis 2019-09-04 no assertion criteria provided literature only

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