rs118203943
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_000046.5(ARSB):c.629A>G(p.Tyr210Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000221 in 1,613,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y210H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000046.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARSB | NM_000046.5 | c.629A>G | p.Tyr210Cys | missense_variant | 3/8 | ENST00000264914.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARSB | ENST00000264914.10 | c.629A>G | p.Tyr210Cys | missense_variant | 3/8 | 1 | NM_000046.5 | P1 | |
ARSB | ENST00000396151.7 | c.629A>G | p.Tyr210Cys | missense_variant | 4/8 | 1 | |||
ARSB | ENST00000565165.2 | c.629A>G | p.Tyr210Cys | missense_variant | 3/5 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.000158 AC: 24AN: 152214Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000271 AC: 68AN: 251284Hom.: 0 AF XY: 0.000294 AC XY: 40AN XY: 135824
GnomAD4 exome AF: 0.000227 AC: 332AN: 1461728Hom.: 0 Cov.: 31 AF XY: 0.000227 AC XY: 165AN XY: 727174
GnomAD4 genome ? AF: 0.000158 AC: 24AN: 152214Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14AN XY: 74376
ClinVar
Submissions by phenotype
Mucopolysaccharidosis type 6 Pathogenic:8
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.027%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 11939792, 23557332, 8651289). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 1.00). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 17458871, 21514195, 23557332, 24221504, 8651289). A different missense change at the same codon (p.Tyr210His) has been reported to be associated with ARSB related disorder (ClinVar ID: VCV001469785). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | curation | Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova | Jan 01, 2018 | In vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes; PS3); Prevalence of the variant in affected is increased compared with controls (PS4); Reputable source identifies as pathogenic (PP5) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 22, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 1996 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 05, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 210 of the ARSB protein (p.Tyr210Cys). This variant is present in population databases (rs118203943, gnomAD 0.06%). This missense change has been observed in individuals with ARSB-related conditions (PMID: 8651289, 17458871, 21514195, 23557332, 24221504). ClinVar contains an entry for this variant (Variation ID: 885). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ARSB function (PMID: 8651289, 11939792, 23557332). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not provided Pathogenic:6
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 02, 2022 | Published functional studies demonstrate that expression of Y210C mutant cell lines results in approximately 2% residual arylsulfatase activity, supporting a damaging effect (Litjens et al., 1996; Brands et al., 2013).; 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: 21917494, 15324318, 28552677, 21791832, 23657977, 24373060, 24221504, 23557332, 8651289, 14974081, 22441840, 22133300, 24389823, 18486607, 17458871, 30118150, 33209960, 31589614, 21514195) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 25, 2013 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2017 | - - |
ARSB-related condition Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 22, 2024 | The ARSB c.629A>G variant is predicted to result in the amino acid substitution p.Tyr210Cys. This variant has been reported to be causative for mucopolysaccharidosis VI syndrome (see for example Litjens et al 1996. PubMed ID: 8651289; Brands et al. 2013. PubMed ID: 23557332; Jurecka. 2014. PubMed ID: 24221504). This variant is reported in 0.056% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. - |
Metachromatic leukodystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 02, 2017 | Variant summary: The ARSB c.629A>G (p.Tyr210Cys) variant located in the Sulfatase, N-termail (via InterPro) involves the alteration of a conserved nucleotide and 5/5 in silico tools predict a damaging outcome for this variant. A functional study, Brands_2013, supports these predictions by observing the variant to cause a significant decrease in ARSB activity in comparison to wild type. This variant was found in 75/277016 control chromosomes (gnomAD), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000569 (72/126548), which does not exceed the estimated maximal expected allele frequency of a pathogenic ARSB variant (0.0022361). Multiple publications have cited the variant homozygously and in compound heterozygosity in affected individuals and indicated the variant to be one of the of most common mutations (Karageorgos_2007). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at