Submissions for variant NM_000263.4(NAGLU):c.170C>G (p.Ala57Gly)

gnomAD frequency: 0.00032  dbSNP: rs181735466

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000291577	SCV000402900	uncertain significance	Mucopolysaccharidosis, MPS-III-B	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000823550	SCV000964412	uncertain significance	Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V	2022-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 57 of the NAGLU protein (p.Ala57Gly). 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 variant has not been reported in the literature in individuals affected with NAGLU-related conditions. ClinVar contains an entry for this variant (Variation ID: 323293). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002521108	SCV003545711	uncertain significance	Inborn genetic diseases	2021-01-13	criteria provided, single submitter	clinical testing	The c.170C>G (p.A57G) alteration is located in exon 1 (coding exon 1) of the NAGLU gene. This alteration results from a C to G substitution at nucleotide position 170, causing the alanine (A) at amino acid position 57 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV000291577	SCV001458026	uncertain significance	Mucopolysaccharidosis, MPS-III-B	2019-11-11	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001699452	SCV001924521	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001699452	SCV001963281	uncertain significance	not provided		no assertion criteria provided	clinical testing