rs104894642
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000199.5(SGSH):c.383C>T(p.Pro128Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,612,548 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P128P) has been classified as Likely benign.
Frequency
Consequence
NM_000199.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.383C>T | p.Pro128Leu | missense_variant | 4/8 | ENST00000326317.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SGSH | ENST00000326317.11 | c.383C>T | p.Pro128Leu | missense_variant | 4/8 | 1 | NM_000199.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152190Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249978Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135494
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1460358Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9AN XY: 726496
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152190Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74348
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-III-A Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 16, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 06, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 128 of the SGSH protein (p.Pro128Leu). This variant is present in population databases (rs104894642, gnomAD 0.003%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IIIA (PMID: 9554748, 12702166). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 5110). 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: 10727844). 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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2003 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at