ClinVar Miner

Submissions for variant NM_000263.4(NAGLU):c.1336G>A (p.Glu446Lys)

dbSNP: rs114625063
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centogene AG - the Rare Disease Company RCV001250253 SCV001424458 pathogenic Mucopolysaccharidosistype IIIB criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003767969 SCV004571059 pathogenic Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V 2024-01-19 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 446 of the NAGLU protein (p.Glu446Lys). This variant is present in population databases (rs114625063, gnomAD 0.0009%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IIIB (PMID: 33083013). ClinVar contains an entry for this variant (Variation ID: 553423). 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: 14984474, 29979746). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV003767969 SCV005646081 likely pathogenic Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V 2024-06-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000668870 SCV005725694 pathogenic Mucopolysaccharidosis, MPS-III-B 2024-11-26 criteria provided, single submitter clinical testing Variant summary: NAGLU c.1336G>A (p.Glu446Lys) results in a conservative amino acid change located in the Alpha-N-acetylglucosaminidase, tim-barrel domain (IPR024733) 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 4e-06 in 249170 control chromosomes. c.1336G>A has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B)(e.g. Beesley_2004, Cheema_2020). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (e.g. Beesley_2004, Clark_2018). The most pronounced variant effect results in <10% of normal activity. The following publications have been ascertained in the context of this evaluation (PMID: 14984474, 33083013, 29979746). ClinVar contains an entry for this variant (Variation ID: 553423). Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl RCV000668870 SCV000793543 uncertain significance Mucopolysaccharidosis, MPS-III-B 2017-08-18 flagged submission clinical testing

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