Submissions for variant NM_000263.4(NAGLU):c.1876C>T (p.Arg626Ter)

gnomAD frequency: 0.00013  dbSNP: rs104894591

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000153533	SCV000203061	pathogenic	not provided	2013-12-19	criteria provided, single submitter	clinical testing
Counsyl	RCV000001627	SCV000789321	pathogenic	Mucopolysaccharidosis, MPS-III-B	2017-01-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000802847	SCV000942693	pathogenic	Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V	2024-08-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg626*) in the NAGLU gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 118 amino acid(s) of the NAGLU protein. 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 premature translational stop signal has been observed in individuals with mucopolysaccharidosis (PMID: 8650226, 9832037, 10094189). ClinVar contains an entry for this variant (Variation ID: 1561). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000001627	SCV001362138	pathogenic	Mucopolysaccharidosis, MPS-III-B	2019-11-11	criteria provided, single submitter	clinical testing	Variant summary: NAGLU c.1876C>T (p.Arg626X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.2e-05 in 229530 control chromosomes. c.1876C>T has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) (Beesley_1998, Weber_1999, Zhao_1996, Zhao_1998). These data indicate that the variant is very likely to be associated with disease. No experimental evidence demonstrating an impact on protein function was ascertained. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000001627	SCV001976823	pathogenic	Mucopolysaccharidosis, MPS-III-B	2021-10-05	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5
Fulgent Genetics, Fulgent Genetics	RCV000802847	SCV002789944	pathogenic	Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V	2022-02-26	criteria provided, single submitter	clinical testing
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV000001627	SCV005397726	pathogenic	Mucopolysaccharidosis, MPS-III-B	2024-04-22	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (C>T) at position 1876 of the coding sequence of the NAGLU gene that changes the arginine codon at position 626 to a premature termination signal. This variant occurs in exon 6 of 6 of the NAGLU gene and though it is not expected to undergo nonsense mediated decay, this variant will truncate the final 106 amino acids of the alpha-N-acetylglucosaminidase domain (UniProt). This is a previously reported variant (ClinVar 1561) that has been observed in homozygous and compound heterozygous individuals affected by mucopolysaccharidosis type IIIB (PMID: 8650226, 9443875, 9832037, 10094189, 14984474). This variant is present in 16 of 381708 alleles (0.0042%) in the gnomAD population dataset. Functional studies have demonstrated that the enzymatic activity of the protein generated from this variant is significantly reduced relative to the wildtype protein (PMID: 29979746). Based upon the evidence, we consider this a pathogenic variant. ACMG Criteria: PM2, PM3, PS3, PVS1
Mayo Clinic Laboratories, Mayo Clinic	RCV000153533	SCV005413219	pathogenic	not provided	2024-05-06	criteria provided, single submitter	clinical testing	PM2, PM3, PS3, PVS1_strong
GeneDx	RCV000153533	SCV005421327	pathogenic	not provided	2024-06-06	criteria provided, single submitter	clinical testing	Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 29979746); Nonsense variant predicted to result in protein truncation, as the last 118 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 33195185, 36344724, 33578874, 9443875, 34411609, 9832037, 36840025, 32886284, 23840811, 32054071, 32880920, 28595941, 33147747, 11668611, 10094189, 14984474, 29979746, 8650226)
OMIM	RCV000001627	SCV000021783	pathogenic	Mucopolysaccharidosis, MPS-III-B	1996-06-11	no assertion criteria provided	literature only
Natera, Inc.	RCV000001627	SCV001463394	pathogenic	Mucopolysaccharidosis, MPS-III-B	2020-09-16	no assertion criteria provided	clinical testing