rs764057581
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_000199.5(SGSH):c.1167C>A(p.Asn389Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,461,764 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. N389S) 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 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SGSH | NM_000199.5 | c.1167C>A | p.Asn389Lys | missense_variant | 8/8 | ENST00000326317.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SGSH | ENST00000326317.11 | c.1167C>A | p.Asn389Lys | missense_variant | 8/8 | 1 | NM_000199.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251050Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135866
GnomAD4 exome AF: 0.0000198 AC: 29AN: 1461764Hom.: 0 Cov.: 34 AF XY: 0.0000206 AC XY: 15AN XY: 727170
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-III-A Pathogenic:5
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 26, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 17, 2023 | This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 389 of the SGSH protein (p.Asn389Lys). This variant is present in population databases (rs764057581, gnomAD 0.004%). This missense change has been observed in individuals with mucopolysaccharidosis type III (PMID: 11903343, 21061399, 34991944). ClinVar contains an entry for this variant (Variation ID: 550465). 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. This variant disrupts the p.Asn389 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22976768). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 02, 2023 | Variant summary: SGSH c.1167C>A (p.Asn389Lys) results in a non-conservative amino acid change in 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 2e-05 in 251050 control chromosomes (gnomAD). c.1167C>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A; e.g. Bunge_1997, Valstar_2010, Wijburg_2022). In addition, the variant has also been reported in heterozygous state in individuals with a clinical phenotype of neuronal ceroid lipofuscinosis (DiFruscio_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, a different missense affecting the same codon (p.Asn389Ser) is classified as pathogenic by our laboratory, indicating that this residue is clinically important. The following publications have been ascertained in the context of this evaluation (PMID: 9401012, 9744479, 11668611, 21061399, 24816101, 26075876, 25807448, 32036093). Four other submitters have cited 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 18, 2020 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | SGSH: PM3:Very Strong, PM2, PM5, PP4 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at