Submissions for variant NM_000263.4(NAGLU):c.1694G>A (p.Arg565Gln) (rs104894598)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000433629	SCV000521202	pathogenic	not provided	2016-09-28	criteria provided, single submitter	clinical testing	The R565Q variant in the NAGLU gene has been reported previously in mucopolysaccharidosis type IIIB, in affected individuals who were compound heterozygous for the R565Q variant and another variant (Bunge et al., 1999; Valstar et al., 2010; Héron et al., 2011; Tang et al., 2013). The R565Q variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R565Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same codon (R565W, R565P, R565L) have been reported in the Human Gene Mutation Database in association with mucopolysaccharidosis type IIIB (Stenson et al., 2014), supporting the functional importance of this codon. We interpret R565Q as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America	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.
Invitae	RCV001043861	SCV001207628	pathogenic	Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease, axonal type 2V	2019-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 565 of the NAGLU protein (p.Arg565Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs104894598, ExAC 0.006%). This variant has been observed in combination with another NAGLU variant in individuals affected with mucopolysaccharidosis type III (PMID: 9950362, 20852935, 23380547, 28751108). ClinVar contains an entry for this variant (Variation ID: 30795). 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: 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 Praxis fuer Humangenetik Tuebingen	RCV000433629	SCV001246601	pathogenic	not provided	2019-11-01	criteria provided, single submitter	clinical testing
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