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

gnomAD frequency: 0.00004  dbSNP: rs147036053

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779220	SCV000915763	pathogenic	Mucopolysaccharidosis, MPS-III-B	2024-09-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000806351	SCV000946343	pathogenic	Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V	2024-02-05	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 634 of the NAGLU protein (p.Glu634Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 20852935, 27590925; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 632282). 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) has been performed at Invitae 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. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
PreventionGenetics, part of Exact Sciences	RCV003396352	SCV004120149	pathogenic	NAGLU-related disorder	2023-07-28	criteria provided, single submitter	clinical testing	The NAGLU c.1900G>A variant is predicted to result in the amino acid substitution p.Glu634Lys. This variant was reported in the compound heterozygous state in individuals with Sanfilippo syndrome B (MPS IIIB) (Table 1, Valstar et al 2010. PubMed ID: 20852935; Table 1, Clark et al. 2018. PubMed ID: 29979746; Table 1, Meijer et al. 2016. PubMed ID: 26907177). Of note, this variant has been reported to be associated attenuated/slow progressing MPS IIIB (Wagner et al. 2019. PubMed ID: 31536183; Valstar et al 2010. PubMed ID: 20852935).This variant is reported in 0.0033% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-40695924-G-A). In ClinVar, this variant has conflicting interpretations ranging from uncertain (1) to pathogenic (2) (https://www.ncbi.nlm.nih.gov/clinvar/variation/632282/). Taken together we interpret this variant as pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000779220	SCV005418206	likely pathogenic	Mucopolysaccharidosis, MPS-III-B		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3_Moderate+PM3_Strong+PP4
GeneDx	RCV005241400	SCV005888852	likely pathogenic	not provided	2024-09-16	criteria provided, single submitter	clinical testing	Reported with a second NAGLU variant in multiple patients with a diagnosis of MPS IIIB in published literature (PMID: 26907177, 27590925, 20852935, 29661560); Identified in two siblings with diagnoses of MPS IIIB who had biochemical testing that was diagnostic and consistent with the results seen in other patients with pathogenic variants in this gene (PMID: 26907177, 20852935); Published functional studies demonstrate a damaging effect, including decreased enzymatic activity (PMID: 29979746); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20852935, 27590925, 26907177, 29661560, 29979746)
GeneReviews	RCV001030810	SCV001194299	not provided	Mucopolysaccharidosis		no assertion provided	literature only