ClinVar Miner

Submissions for variant NM_000263.4(NAGLU):c.1693C>T (p.Arg565Trp) (rs104894597)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000001633 SCV000402914 pathogenic Mucopolysaccharidosis, MPS-III-B 2017-04-27 criteria provided, single submitter clinical testing The NAGLU c.1693C>T (p.Arg565Trp) variant has been reported to account for 3.4% of variant alleles in individuals with mucopolysaccharidosis type III and is associated with an attenuated phenotype (Yogalingham et al. 2001). The p.Arg565Trp variant has been reported in ten studies and is found in a total of 17 individuals including in four individuals in a homozygous state, in 11 individuals (including three sibling pairs) in a compound heterozygous state, and in two individuals in a heterozygous state (Beesley et al. 1998; Weber et al. 1999; Col et al. 2001; Tanaka et al. 2002; Lee-Chen et al. 2002; Beesley et al. 2005; Mangas et al. 2008; Valstar et al. 2010; Tang et al. 2013; Shi et al. 2014). The p.Arg565Trp variant was absent from 474 ethnically matched control chromosomes and is reported at a frequency of 0.00035 in the East Asian population of the Exome Aggregation Consortium. The p.Arg565Trp variant showed a drastic reduction in NAGLU enzyme activity despite normal mRNA levels in four studies (Lee-Chen et al. 2002; Mangas et al. 2008; Tang et al. 2013; Shi et al. 2014). Structural modelling showed that the p.Arg565Trp variant is located at the alpha-helical domain next to the enzyme binding site (Shi et al. 2014). Based on the collective evidence, the p.Arg565Trp variant is classified as pathogenic for mucopolysaccharidosis type III. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000001633 SCV000919839 pathogenic Mucopolysaccharidosis, MPS-III-B 2017-10-02 criteria provided, single submitter clinical testing Variant summary: The NAGLU c.1693C>T (p.Arg565Trp) variant located in the Alpha-N-acetylglucosaminidase, C-terminal domain (IPR024732) (InterPro) causes a missense change involving a conserved nucleotide and 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Functional enzymatic studies showed very low to no alpha-N-acetyl-glucosaminidase activity in peripheral leukocytes and cultured fibroblasts of homozygotes and compound heterozygotes (Tanaka_2002 and Shi_2014). The variant was found in 10/274834 control chromosomes (gnomAD) at a frequency of 0.0000364, which does not exceed the estimated maximal expected allele frequency of a pathogenic NAGLU variant (0.0025). This variant was reported in multiple patients diagnosed with Sanfilippo syndrome (mucopolysaccharidosis IIIB), associated with a severe phenotype (Beesley_2005, Weber_Genet_1999, Shi_2014). In addition, a clinical diagnostic laboratory and a reputable database classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Mendelics RCV000001633 SCV001140449 pathogenic Mucopolysaccharidosis, MPS-III-B 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV001223228 SCV001395367 pathogenic Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease, axonal type 2V 2019-10-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 565 of the NAGLU protein (p.Arg565Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs104894597, ExAC 0.04%). This variant has been observed to segregate with mucopolysaccharidosis type IIIB in a family and has been reported to be homozygous or in combination with another NAGLU variant in unrelated individuals with this disease (PMID: 25466957, 12202988, 9832037). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1567). 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"). This variant disrupts the p.Arg565 amino acid residue in NAGLU. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9950362, 20852935, 28751108). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000001633 SCV000021789 pathogenic Mucopolysaccharidosis, MPS-III-B 1999-01-01 no assertion criteria provided literature only
Counsyl RCV000001633 SCV000790179 pathogenic Mucopolysaccharidosis, MPS-III-B 2017-03-07 no assertion criteria provided clinical testing

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