rs753355844
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_152419.3(HGSNAT):c.1411G>A(p.Glu471Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,608 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. E471Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_152419.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HGSNAT | NM_152419.3 | c.1411G>A | p.Glu471Lys | missense_variant | 14/18 | ENST00000379644.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HGSNAT | ENST00000379644.9 | c.1411G>A | p.Glu471Lys | missense_variant | 14/18 | 2 | NM_152419.3 | P3 | |
HGSNAT | ENST00000521576.1 | c.562G>A | p.Glu188Lys | missense_variant | 5/9 | 2 | A2 | ||
HGSNAT | ENST00000524016.5 | c.517G>A | p.Glu173Lys | missense_variant | 5/7 | 4 | |||
HGSNAT | ENST00000520678.1 | n.344G>A | non_coding_transcript_exon_variant | 4/4 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249268Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135222
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461608Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7AN XY: 727094
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-III-C Pathogenic:2
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Feb 13, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Mucopolysaccharidosis, MPS-III-C;C4225287:Retinitis pigmentosa 73 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 12, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 471 of the HGSNAT protein (p.Glu471Lys). This variant is present in population databases (rs753355844, gnomAD 0.003%). This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 17033958, 18024218, 19479962). This variant is also known as p.E499K. ClinVar contains an entry for this variant (Variation ID: 265483). 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 HGSNAT protein function. Experimental studies have shown that this missense change affects HGSNAT function (PMID: 20583299). 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:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 12, 2021 | Published functional studies demonstrate the variant causes negligible heparan acetyl CoA: alpha-glucosaminide N-acetyltransferase (HGSNAT) enzyme activity and caused misfolding of the HGSNAT protein and retention in the endoplasmic reticulum (Fedele et al. 2010; Feldhammer et al. 2009); Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 17033958, 19823584, 18024218, 19479962, 32770643, 31228227, 20583299) - |
Sanfilippo syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 05, 2017 | Variant summary: The HGSNAT c.1411G>A (p.Glu471Lys) variant causes the change of "an acidic residue for a basic one just inside the lysosomal luman (Feldhammer_2009)" involving the alteration of a conserved nucleotide and 3/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a damaging outcome for this variant . This variant was found in 1/120760 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic HGSNAT variant (0.001). The variant was reported in the literature in MPS type IIIC patients both in the homozygous state and in the compound heterozygous state with other pathogenic variants. Additionally, the variant expressed in various cell model systems was shown to have significantly decreased enzyme activity, and to result in production of misfolded HGSNAT protein that is abnormally glycosylated and not targeted to the lysosome (Fedele_2010, Feldhammer_2009). One clinical diagnostic laboratory 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