Submissions for variant NM_000263.4(NAGLU):c.1694G>A (p.Arg565Gln)

gnomAD frequency: 0.00004  dbSNP: rs104894598

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000433629	SCV000521202	pathogenic	not provided	2024-03-08	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11668611, 20852935, 9950362, 16151907, 21937992, 26907177, 21204211, 23380547, 28751108, 29979746, 30426380, 23430803, 15933803, 15300983, 10094189, 28844463, 28101780, 31589614, 33747789, 33552644)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590258	SCV000696367	pathogenic	Sanfilippo syndrome	2016-06-17	criteria provided, single submitter	clinical testing	Variant summary: The NAGLU c.1694G>A (p.Arg565Gln) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). Arg565 is highly conserved across species, and two other mutations have been reported at the Arg565 codon (R565Q, R565P) (Beesley et al 1998; Bunge et al 1999; Weber et al 1999), which suggests that this codon is a mutational hotspot in the NAGLU gene. This variant was found in 4/115194 control chromosomes at a frequency of 0.0000347, which does not exceed the estimated maximal expected allele frequency of a pathogenic NAGLU variant (0.0025). The variant has been identified in multiple MPS3B patients in compound heterozygous state and has been shown to co-segregate with disease in at least one family (Tang_CCA_2013). Compound heterozygous patients have been shown to have <10% of normal NAGLU activity. In addition, OMIM classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001043861	SCV001207628	pathogenic	Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 565 of the NAGLU protein (p.Arg565Gln). This variant is present in population databases (rs104894598, gnomAD 0.009%). This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 9950362, 20852935, 23380547, 28751108). ClinVar contains an entry for this variant (Variation ID: 30795). 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%. 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: 10094189, 15933803, 23430803). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000433629	SCV001246601	pathogenic	not provided	2019-11-01	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000023780	SCV005046814	pathogenic	Mucopolysaccharidosis, MPS-III-B	2024-05-06	criteria provided, single submitter	clinical testing	A homozygous variant in exon 6 of the NAGLU gene that results in the amino acid substitution of glutamine for arginine at codon 565 was detected. The observed variant c.1694G>A has not been reported in the 1000 genomes database and has MAF of 0.0044% in the gnomAD database. The in silico predictions is damaging by MutationTaster and SIFT, Polyphen2 and DANN. In summary, the variant meets our criteria to be classified as pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000023780	SCV005051873	pathogenic	Mucopolysaccharidosis, MPS-III-B	2024-02-01	criteria provided, single submitter	curation
OMIM	RCV000023780	SCV000045071	pathogenic	Mucopolysaccharidosis, MPS-III-B	2011-09-21	no assertion criteria provided	literature only
Counsyl	RCV000023780	SCV000788474	likely pathogenic	Mucopolysaccharidosis, MPS-III-B	2017-09-29	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000023780	SCV002093276	pathogenic	Mucopolysaccharidosis, MPS-III-B	2020-08-17	no assertion criteria provided	clinical testing