Submissions for variant NM_000263.4(NAGLU):c.1208T>C (p.Ile403Thr)

gnomAD frequency: 0.00001  dbSNP: rs796052122

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000423370	SCV000516177	likely pathogenic	not provided	2022-07-05	criteria provided, single submitter	clinical testing	Observed in heterozygous state in multiple affected individuals from a single family with late-onset painful sensory neuropathy, suggesting possible autosomal dominant inheritance. Further research is necessary to clarify this association (Ttreault et al., 2015); Not observed at 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: Michael2016[Article], 20852935, 25818867)
Invitae	RCV001852433	SCV002272508	likely pathogenic	Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V	2023-08-07	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 204585). This missense change has been observed in individual(s) with autosomal dominant neuropathy and/or autosomal recessive mucopolysaccharidosis type III (PMID: 20852935, 25818867). This variant is present in population databases (rs796052122, gnomAD 0.002%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 403 of the NAGLU protein (p.Ile403Thr).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479050	SCV004223636	pathogenic	Mucopolysaccharidosis, MPS-III-B	2023-11-10	criteria provided, single submitter	clinical testing	Variant summary: NAGLU c.1208T>C (p.Ile403Thr) results in a non-conservative amino acid change located in the Alpha-N-acetylglucosaminidase, tim-barrel domain (IPR024733) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251378 control chromosomes (gnomAD). c.1208T>C has been reported in the literature in an individual affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) who was reported as compound heterozygous with another pathogenic variant (Valstar_2010). It was also to segregate in a large family with an autosomal dominant late-onset painful axonal neuropathy (Tetreault_2015), and the individuals with the variant had significantly lower NAGLU enzymatic activity in leukocytes than the family members with the wild type allele. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 20852935, 25818867). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, three of which provided an interpretation. All three of these submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000186582	SCV000240158	pathogenic	Charcot-Marie-Tooth disease axonal type 2V	2015-06-01	no assertion criteria provided	literature only
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000186582	SCV000266395	not provided	Charcot-Marie-Tooth disease axonal type 2V	2016-03-24	no assertion provided	literature only