rs104894638
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000199.5(SGSH):c.449G>A(p.Arg150Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,318 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R150W) has been classified 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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SGSH | NM_000199.5 | c.449G>A | p.Arg150Gln | missense_variant | 4/8 | ENST00000326317.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SGSH | ENST00000326317.11 | c.449G>A | p.Arg150Gln | missense_variant | 4/8 | 1 | NM_000199.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152182Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000200 AC: 5AN: 250524Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135752
GnomAD4 exome AF: 0.0000342 AC: 50AN: 1461136Hom.: 0 Cov.: 33 AF XY: 0.0000261 AC XY: 19AN XY: 726870
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152182Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74338
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-III-A Pathogenic:8
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 06, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 17, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 02, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 04, 2018 | Variant summary: SGSH c.449G>A (p.Arg150Gln) results in a conservative amino acid change located in the Sulfatase, N-terminal domain of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 276994 control chromosomes (gnomAD and publication data). c.449G>A has been reported in the literature as a homozygous and compound heterozygous allele in multiple individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (Bunge 1997, Di Natale 1998, Heron 2010, Valstar 2010). 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 enzyme activity, showing that the variant results in <10% of normal activity (Esposito 2000). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1998 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 150 of the SGSH protein (p.Arg150Gln). This variant is present in population databases (rs104894638, gnomAD 0.005%). This missense change has been observed in individuals with mucopolysaccharidosis type III (PMID: 9401012, 9554748, 9744479, 11343308, 21061399, 21204211). ClinVar contains an entry for this variant (Variation ID: 5113). 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 SGSH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SGSH function (PMID: 10727844). This variant disrupts the p.Arg150 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been observed in individuals with SGSH-related conditions (PMID: 11182930, 21204211), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 19, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at