17-80217084-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_000199.5(SGSH):c.197C>G(p.Ser66Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,600,772 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 (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

SGSH
NM_000199.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:23O:1

Conservation

PhyloP100: 9.05

Variant links:

Genes affected

SGSH (HGNC:10818): (N-sulfoglucosamine sulfohydrolase) This gene encodes the enzyme sulfamidase; one of several enzymes involved in the lysosomal degradation of heparan sulfate. Mutations in this gene are associated with the lysosomal storage disease mucopolysaccaridosis IIIA, also known as Sanfilippo syndrome A, which results from impaired degradation of heparan sulfate. Transcripts of varying sizes have been reported but their biological validity has not been determined. [provided by RefSeq, Jun 2017]

SGSH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.88

PP5

Variant 17-80217084-G-C is Pathogenic according to our data. Variant chr17-80217084-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 5111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80217084-G-C is described in Lovd as [Pathogenic]. Variant chr17-80217084-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGSH	NM_000199.5 link	c.197C>G	p.Ser66Trp	missense_variant	Exon 2 of 8	ENST00000326317.11	NP_000190.1	P51688

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGSH	ENST00000326317.11 link	c.197C>G	p.Ser66Trp	missense_variant	Exon 2 of 8	1	NM_000199.5	ENSP00000314606.6		P51688

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000928

AC:

AN:

226198

Hom.:

AF XY:

0.0000896

AC XY:

AN XY:

122814

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000205

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000161

AC:

233

AN:

1448528

Hom.:

Cov.:

AF XY:

0.000150

AC XY:

108

AN XY:

719644

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000397

Gnomad4 NFE exome

AF:

0.000201

Gnomad4 OTH exome

AF:

0.000134

GnomAD4 genome

AF:

0.000105

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000157

Hom.:

Bravo

AF:

0.000102

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000746

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:23Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-A

Pathogenic:17

Mar 29, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 24, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000199.3(SGSH):c.197C>G(S66W) is classified as pathogenic in the context of mucopolysaccharidosis type IIIA. Sources cited for classification include the following: PMID 10601282, 15542396, 9158154, 11182930 and 9554748. Classification of NM_000199.3(SGSH):c.197C>G(S66W) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 66 of the SGSH protein (p.Ser66Trp). This variant is present in population databases (rs104894637, gnomAD 0.02%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IIIA (PMID: 9158154, 9285796, 9554748, 15542396, 21061399, 22976768). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5111). 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 SGSH protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SGSH function (PMID: 10601282, 15542396). For these reasons, this variant has been classified as Pathogenic. -

Mar 27, 2020

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4, PP3 -

Mar 28, 2024

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a single nucleotide substitution (C>G) at position 197 of the coding sequence of the SGSH gene that results in a serine to tryptophan amino acid change at residue 66 of the N-sulfoglucosamine sulfohydrolase protein. This is a previously reported variant (ClinVar 5111) that has been commonly observed in homozygous or compound heterozygous state in individuals affected by Sanfilippo syndrome type A (PMID: 9158154, 9285796, 9554748). This variant is present in 249 of 1600772 alleles (0.01555%) in the gnomAD v4.0.0 population dataset. Multiple bioinformatic tools predict that this amino acid change would be damaging, and the Ser66 residue at this position is highly conserved across the vertebrate species examined. Functional studies indicate that the variant protein has 15% or less activity (PMID: 10601282, 15542396). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM3, PP3, PS3, PS4 -

Jan 01, 2019

Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

PS3: Low in vitro enzymatic activity. PP1: Cosegregation with disease in multiple affected family members (strong evidence). PM2: Very low frequency in GnomAD. PP5: reputable source report variant as pathogenic. -

Feb 09, 2024

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 30, 2020

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as disease-causing PMIDs 10601282, 9554748, 29023963, 21228398, 9158154, 24816101, 15542396, 10521831, 25807448. -

Sep 06, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 13, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 22, 2023

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 18, 2019

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SGSH: PM3:Very Strong, PM2, PP3, PS3:Supporting -

Nov 04, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect with reduced protein quantity and activity (Perkins et al., 1999; Montfort et al., 2004); 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: 10521831, 25807448, 24816101, 15542396, 31980526, 9554748, 10601282, 9158154, 21228398, 29023963, 30809705, 34440436, 34349725, 31589614) -

Sep 23, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Feb 19, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.197C>G (p.S66W) alteration is located in exon 2 (coding exon 2) of the SGSH gene. This alteration results from a C to G substitution at nucleotide position 197, causing the serine (S) at amino acid position 66 to be replaced by a tryptophan (W). Based on data from the Genome Aggregation Database (gnomAD) database, the SGSH c.197C>G alteration was observed in 0.01% (23/257594) of total alleles studied, with a frequency of 0.02% (23/117902) in the European (non-Finnish) subpopulation. This mutation has been detected as heterozygous, compound heterozygous, and homozygous, in individuals with typical severe presentations of Mucopolysaccaridosis type IIIA (Sanfilippo syndrome type A) (Blanch, 1997; Di Natale, 1998; Valstar, 2010; Ouesleti, 2011; Delgadillo, 2013; Shapiro, 2016; Knottnerus, 2017; Zanetti, 2019). In addition, one functional study showed that this mutation results in a drastically reduced level of functional protein as well as lowered specific activity (Perkins, 1999). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for the p.S66W alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

SGSH-related disorder

Pathogenic:1

Dec 12, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SGSH c.197C>G variant is predicted to result in the amino acid substitution p.Ser66Trp. This variant was reported in multiple individuals mucopolysaccharidosis type IIIA (Sanfilippo A) (Blanch. 1997. PubMed ID: 9158154; Knottnerus. 2017. PubMed ID: 29023963; Barone. 2021. PubMed ID: 34349725; Table S4, Barbosa-Gouveia. 2021. PubMed ID: 34440436). Functional in vitro studies found this variant has reduced expression and residual activity (Perkins. 1999. PubMed ID: 10601282). This variant is reported in 0.020% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Sanfilippo syndrome

Pathogenic:1

Aug 02, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The SGSH c.197C>G (p.Ser66Trp) variant involves the alteration of a conserved nucleotide located in the Alkaline-phosphatase-like domain of the protein (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 23/251298 control chromosomes at a frequency of 0.0000915, which does not exceed the estimated maximal expected allele frequency of a pathogenic SGSH variant (0.0032275). This variant has been reported in numerous patients both homozygously and compound heterozygously. Functional study showed variant with 10% of WT enzyme activity (Montfort_MGM_2004) In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Mucopolysaccharidosis

Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.27

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.88

MetaSVM

Pathogenic

1.1

Sift4G

Benign

0.39

Vest4

0.69

MVP

0.92

ClinPred

0.87

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over