chr17-80210831-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000199.5(SGSH):c.1130G>A(p.Arg377His) variant causes a missense change. The variant allele was found at a frequency of 0.0000161 in 1,613,840 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R377C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000199.5 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 |
---|---|---|---|---|---|---|---|
SGSH | NM_000199.5 | c.1130G>A | p.Arg377His | missense_variant | 8/8 | ENST00000326317.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SGSH | ENST00000326317.11 | c.1130G>A | p.Arg377His | missense_variant | 8/8 | 1 | NM_000199.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 250948Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135810
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461668Hom.: 0 Cov.: 34 AF XY: 0.0000179 AC XY: 13AN XY: 727122
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74334
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-III-A Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 377 of the SGSH protein (p.Arg377His). This variant is present in population databases (rs746037899, gnomAD 0.003%). This missense change has been observed in individual(s) with mucopolysaccharidosis IIIA (PMID: 29023963, 31718697). ClinVar contains an entry for this variant (Variation ID: 1297691). 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%. This variant disrupts the p.Arg377 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9554748, 12000360, 19099774, 21910976). 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 | May 16, 2022 | Variant summary: SGSH c.1130G>A (p.Arg377His) results in a non-conservative amino acid change in the encoded protein sequence. This variant is predicted to impact the structure of the SGSH protein due to loss of a buried salt bridge with Asp 477 and of hydrogen bonds to Ser 366 and Met 376 (Sidhu_2014). 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 4e-06 in 250948 control chromosomes. c.1130G>A has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (example, Bunge_1997, Valstar_2010, Knottnerus_2017, Nijmeijer_2019). 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories 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 | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Aug 08, 2022 | A compound heterozygous missense variation in exon 8 and exon 7 of the SGSH gene that results in the amino acid substitution of Histidine for Arginine at codon377 was detected. The observed variant c.1130G>A(p.Arg377His) has a minor allele frequency of 0.0003%, and 0.0008% in the 1000 genomes and gnomAD databases. Alternative variant chr17:78184631 GāA (Arg377Cys) is classified Pathogenic by UniProt Variants (and confirmed using ACMG). The in silico prediction of the variant is benign by DANN, SIFT, LRT ,FATHMM-XF, MutPred and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 16, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 20, 2023 | - - |
not provided Pathogenic:2
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at