Submissions for variant NM_000046.5(ARSB):c.406G>A (p.Ala136Thr)

gnomAD frequency: 0.00045  dbSNP: rs146704780

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000302463	SCV000458389	uncertain significance	Mucopolysaccharidosis type 6	2018-01-13	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	RCV000302463	SCV000949403	uncertain significance	Mucopolysaccharidosis type 6	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 136 of the ARSB protein (p.Ala136Thr). This variant is present in population databases (rs146704780, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ARSB-related conditions. ClinVar contains an entry for this variant (Variation ID: 354314). 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 ARSB 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252104	SCV002523327	uncertain significance	See cases	2019-11-01	criteria provided, single submitter	clinical testing	ACMG classification criteria: PP3
Mayo Clinic Laboratories, Mayo Clinic	RCV003480617	SCV004227089	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing	PM2
Natera, Inc.	RCV000302463	SCV001458080	uncertain significance	Mucopolysaccharidosis type 6	2019-10-28	no assertion criteria provided	clinical testing