rs121908282
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_152419.3(HGSNAT):c.848C>T(p.Pro283Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,612,400 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_152419.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HGSNAT | ENST00000379644.9 | c.848C>T | p.Pro283Leu | missense_variant | Exon 9 of 18 | 2 | NM_152419.3 | ENSP00000368965.4 | ||
HGSNAT | ENST00000520704.1 | n.*297C>T | non_coding_transcript_exon_variant | Exon 10 of 10 | 1 | ENSP00000429109.1 | ||||
HGSNAT | ENST00000520704.1 | n.*297C>T | 3_prime_UTR_variant | Exon 10 of 10 | 1 | ENSP00000429109.1 | ||||
HGSNAT | ENST00000522082.5 | c.89C>T | p.Pro30Leu | missense_variant | Exon 2 of 6 | 4 | ENSP00000430151.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152116Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000283 AC: 7AN: 246918Hom.: 0 AF XY: 0.0000373 AC XY: 5AN XY: 133948
GnomAD4 exome AF: 0.0000110 AC: 16AN: 1460284Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 6AN XY: 726294
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152116Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74302
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-III-C;C4225287:Retinitis pigmentosa 73 Pathogenic:2
- -
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 283 of the HGSNAT protein (p.Pro283Leu). This variant is present in population databases (rs121908282, gnomAD 0.02%). This missense change has been observed in individuals with Mucopolysaccharidosis IIIC (Sanfilippo C Syndrome) (PMID: 17033958, 31228227). This variant is also known as P311L. ClinVar contains an entry for this variant (Variation ID: 1232). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt HGSNAT protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects HGSNAT function (PMID: 19823584, 20583299). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:2
- -
The P283L variant in the HGSNAT gene has been reported previously, using alternate nomenclature P311L, in association with mucopolysaccharidosis IIIC, in an affected individual who was homozygous for the P283L variant, and in an affected individual who was heterozygous for the P283L variant and another HGSNAT variant (Hrebicek et al., 2006). The P283L variant is observed in 3/18754 (0.016%) alleles from individuals of East Asian background, in the ExAC dataset (Lek et al., 2016). The P283L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Functional studies show that P283L has reduced enzyme activity compared to wild type and mislocalization due to incorrect protein folding (Feldhammer et al., 2009; Fedele et al., 2010). We interpret P283L as a likely pathogenic variant. -
Retinal dystrophy Pathogenic:2
- -
- -
Mucopolysaccharidosis, MPS-III-C Pathogenic:1
- -
Sanfilippo syndrome Pathogenic:1
Variant summary: HGSNAT c.848C>T (p.Pro283Leu) results in a non-conservative amino acid change located in the catalytic domain (IPR012429) of 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 2.8e-05 in 246918 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.848C>T has been reported in the literature in both homozygous and compound heterozygous individuals affected with Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome C) (e.g., Hrebicek_2006, Martins_2019). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function, finding that the variant results in <10% of normal activity (e.g., Feldhammer_2009, Fedele_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20583299, 19823584, 17033958, 31228227). Five submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at