chr17-80214264-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000199.5(SGSH):c.571G>A(p.Gly191Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,613,162 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 Likely pathogenic (★★).
Frequency
Consequence
NM_000199.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152206Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000163 AC: 4AN: 245376Hom.: 0 AF XY: 0.0000300 AC XY: 4AN XY: 133518
GnomAD4 exome AF: 0.0000363 AC: 53AN: 1460956Hom.: 0 Cov.: 34 AF XY: 0.0000330 AC XY: 24AN XY: 726742
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152206Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74354
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-III-A Pathogenic:7
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The missense c.571G>A (p.Gly191Arg) variant in the SGSH gene has been observed in individuals with mucopolysaccharidosis type III. Experimental studies have shown that this missense change affects SGSH function (Muschol, Nicole et al.,2004). This variant is reported with the allele frequency (0.001%) in the gnomAD Exomes. It is submitted to ClinVar as Likely Pathogenic/ Pathogenic. The amino acid Glycine at position 191 is changed to a Arginine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid Glycine in SGSH is predicted as conserved by GERP++ and PhyloP across 100 vertebrates Multiple lines of computational evidence (Polyphen - Damaging, SIFT – Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic. -
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This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 191 of the SGSH protein (p.Gly191Arg). This variant is present in population databases (rs753666460, gnomAD 0.01%). This missense change has been observed in individuals with mucopolysaccharidosis type III (PMID: 15146460, 21061399, 23084433, 34813777). ClinVar contains an entry for this variant (Variation ID: 372781). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SGSH protein function. Experimental studies have shown that this missense change affects SGSH function (PMID: 15146460). For these reasons, this variant has been classified as Pathogenic. -
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not provided Pathogenic:1
Published functional studies demonstrate a damaging effect, including inactive or significantly reduced enzymatic activity (Muschol et al., 2004); Not observed at significant frequency in large population cohorts (gnomAD); 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: 24816101, 21061399, 19099774, 25807448, 15146460, 29023963, 34813777, 31069529, 34047372, 34991944) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at