ClinVar Miner

Submissions for variant NM_000263.4(NAGLU):c.1241A>G (p.His414Arg)

gnomAD frequency: 0.00001  dbSNP: rs768814260
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668171 SCV000792729 pathogenic Mucopolysaccharidosis, MPS-III-B 2017-07-11 criteria provided, single submitter clinical testing
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova RCV000668171 SCV000929909 likely pathogenic Mucopolysaccharidosis, MPS-III-B 2019-01-01 criteria provided, single submitter literature only PS3: Low in vitro enzymatic activity. PM2: Very low frequency in GnomAD
Labcorp Genetics (formerly Invitae), Labcorp RCV000819008 SCV000959647 pathogenic Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V 2025-01-07 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 414 of the NAGLU protein (p.His414Arg). This variant is present in population databases (rs768814260, gnomAD 0.008%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IIIB (PMID: 14984474, 22976768). 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: 552833). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NAGLU protein function. Experimental studies have shown that this missense change affects NAGLU function (PMID: 14984474). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV003117471 SCV003798753 pathogenic not provided 2023-02-06 criteria provided, single submitter clinical testing Published functional studies demonstrate significant reduction in enzyme activity compared to wildtype (Clark et al., 2018; Beesley et al., 2004); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16151907, 22976768, 30222014, 10094189, 29979746, 31980526, 30809705, 14984474, 30070758, 11668611, 29661560, 27590925, 21204211, 33578874)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000668171 SCV003844681 pathogenic Mucopolysaccharidosis, MPS-III-B 2023-02-14 criteria provided, single submitter clinical testing Variant summary: NAGLU c.1241A>G (p.His414Arg) results in a non-conservative amino acid change located in the Alpha-N-acetylglucosaminidase, tim-barrel domain (IPR024733) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251322 control chromosomes (gnomAD). c.1241A>G has been reported in the literature as a biallelic genotype in multiple individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B, e.g. Weber_1999, Beesley_2004). These data indicate that the variant is very likely to be associated with disease. The variant was also confirmed to have loss-of-function in vitro, with nearly absent NAGLU activity (e.g. Beesley_2004, Clark_2018). Four ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and three as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV000668171 SCV005051875 pathogenic Mucopolysaccharidosis, MPS-III-B 2024-02-01 criteria provided, single submitter curation
Natera, Inc. RCV000668171 SCV001463387 pathogenic Mucopolysaccharidosis, MPS-III-B 2020-09-16 no assertion criteria provided clinical testing

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