chr5-78969051-G-A
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong
The NM_000046.5(ARSB):c.454C>T(p.Arg152Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000044 in 1,614,012 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. R152Q) 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 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARSB | NM_000046.5 | c.454C>T | p.Arg152Trp | missense_variant | 2/8 | ENST00000264914.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARSB | ENST00000264914.10 | c.454C>T | p.Arg152Trp | missense_variant | 2/8 | 1 | NM_000046.5 | P1 | |
ARSB | ENST00000396151.7 | c.454C>T | p.Arg152Trp | missense_variant | 3/8 | 1 | |||
ARSB | ENST00000565165.2 | c.454C>T | p.Arg152Trp | missense_variant | 2/5 | 1 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251474Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135910
GnomAD4 exome AF: 0.0000410 AC: 60AN: 1461878Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30AN XY: 727242
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152134Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74316
ClinVar
Submissions by phenotype
Mucopolysaccharidosis type 6 Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 10, 2022 | Variant summary: ARSB c.454C>T (p.Arg152Trp) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251474 control chromosomes. c.454C>T has been reported in the literature as a biallelic homozygous/compound heterozygous genotype in multiple individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) (example, Voskoboeva_1994, Karageorgos_2007, Jurecka_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Karageorgos_2007). The most pronounced variant effect results in <10% of normal activity in fibroblasts from an individual with a homozygous genotype. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
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 variant in affected is significantly increased compared to controls (PS4); Very low frequence in GnomAd (PM2);Reputable source identifies as pathogenic (PP5) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 22, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 152 of the ARSB protein (p.Arg152Trp). This variant is present in population databases (no rsID available, gnomAD 0.009%). This missense change has been observed in individuals with mucopolysaccharidosis type VI (PMID: 8125475, 17458871, 23557332, 24221504). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 496789). 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: 23557332). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 02, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 05, 2024 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 09, 2023 | Published functional studies demonstrate significantly decreased ARSB activity compared to wild type and no expression of the mature ARSB enzyme (Brands et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8125475, 31009684, 22441840, 28552677, 23557332, 22133300, 10923267, 17458871, 24875751, 23633437, 30118150, 35118118, 35052464, 33209960, 21917494, 24221504) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 29, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at