Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
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. |
| 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 |