rs759356342
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5
The NM_000046.5(ARSB):c.305G>A(p.Arg102His) variant causes a missense change. The variant allele was found at a frequency of 0.0000316 in 1,424,040 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R102S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000046.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARSB | NM_000046.5 | c.305G>A | p.Arg102His | missense_variant | 1/8 | ENST00000264914.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARSB | ENST00000264914.10 | c.305G>A | p.Arg102His | missense_variant | 1/8 | 1 | NM_000046.5 | P1 | |
ARSB | ENST00000396151.7 | c.305G>A | p.Arg102His | missense_variant | 2/8 | 1 | |||
ARSB | ENST00000565165.2 | c.305G>A | p.Arg102His | missense_variant | 1/5 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000396 AC: 6AN: 151400Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000191 AC: 2AN: 104750Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 60286
GnomAD4 exome AF: 0.0000306 AC: 39AN: 1272640Hom.: 0 Cov.: 31 AF XY: 0.0000271 AC XY: 17AN XY: 626432
GnomAD4 genome ? AF: 0.0000396 AC: 6AN: 151400Hom.: 0 Cov.: 33 AF XY: 0.0000406 AC XY: 3AN XY: 73930
ClinVar
Submissions by phenotype
Mucopolysaccharidosis type 6 Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 102 of the ARSB protein (p.Arg102His). 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 missense change has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 17161971, 17458871). ClinVar contains an entry for this variant (Variation ID: 559766). 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%. Studies have shown that this missense change alters ARSB gene expression (PMID: 17161971). 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. - |
Uncertain significance, criteria provided, single submitter | curation | Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova | Jan 01, 2018 | Absent from GnomAD (PM2) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 25, 2024 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 28, 2021 | Variant summary: ARSB c.305G>A (p.Arg102His) results in a non-conservative amino acid change in 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 1.9e-05 in 104750 control chromosomes. c.305G>A has been reported in the literature in individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome, Karageorgos_MGM_2007, Karageorgos_HumMut_2007). These data do not allow any conclusion about variant significance. Co-occurrence with a pathogenic variant has been reported (ARSB del exon 5), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity (Karageorgos_MGM_2007). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at