chr17-80217061-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000199.5(SGSH):​c.220C>T​(p.Arg74Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000214 in 1,591,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

SGSH
NM_000199.5 missense

Scores

16
2
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22O:1

Conservation

PhyloP100: 5.87
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.966
PP5
Variant 17-80217061-G-A is Pathogenic according to our data. Variant chr17-80217061-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80217061-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SGSHNM_000199.5 linkc.220C>T p.Arg74Cys 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
SGSHENST00000326317.11 linkc.220C>T p.Arg74Cys missense_variant Exon 2 of 8 1 NM_000199.5 ENSP00000314606.6 P51688

Frequencies

GnomAD3 genomes
AF:
0.000204
AC:
31
AN:
152230
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
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:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000397
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000146
AC:
31
AN:
212940
Hom.:
0
AF XY:
0.000173
AC XY:
20
AN XY:
115448
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:
0.000111
Gnomad FIN exome
AF:
0.000249
Gnomad NFE exome
AF:
0.000251
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000215
AC:
309
AN:
1439132
Hom.:
0
Cov.:
31
AF XY:
0.000203
AC XY:
145
AN XY:
714184
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000841
Gnomad4 FIN exome
AF:
0.000226
Gnomad4 NFE exome
AF:
0.000259
Gnomad4 OTH exome
AF:
0.0000672
GnomAD4 genome
AF:
0.000204
AC:
31
AN:
152230
Hom.:
0
Cov.:
33
AF XY:
0.000242
AC XY:
18
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000188
Gnomad4 NFE
AF:
0.000397
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000221
Hom.:
0
Bravo
AF:
0.000102
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000467
AC:
4
ExAC
AF:
0.0000920
AC:
11

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:22Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-A Pathogenic:17
Jun 07, 2017
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 01, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 74 of the SGSH protein (p.Arg74Cys). This variant is present in population databases (rs104894636, gnomAD 0.04%). This missense change has been observed in individuals with MPS type IIIA (PMID: 9285796, 9401012, 22976768, 28844463). ClinVar contains an entry for this variant (Variation ID: 5108). 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, 15146460). This variant disrupts the p.Arg74 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been observed in individuals with SGSH-related conditions (PMID: 9401012, 15542396), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Mar 28, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 26, 2019
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

NM_000199.3(SGSH):c.220C>T(R74C) is classified as pathogenic in the context of mucopolysaccharidosis type IIIA. Sources cited for classification include the following: PMID 9401012, 15146460, 11182930, 18407553, 24314109, 21061399 and 11182930. Classification of NM_000199.3(SGSH):c.220C>T(R74C) 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. -

Jun 16, 2011
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

A Heterozygous missense variation in exon 2 of the SGSH gene that results in the amino acid substitution of Cystine for Arginine at codon 74 was detected. The observed variant c.220C>T (p.Arg74Cys) has not been reported in the 1000 genomes and has a MAF of 0.02% in gnomAD databases. The in silico prediction of the variant are possibly damaging by LRT, SIFT and MutationTaster. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -

Jan 01, 1997
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

May 25, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genomics England Pilot Project, Genomics England
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 07, 2021
Genome-Nilou Lab
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 25, 2021
Centre for Inherited Metabolic Diseases, Karolinska University Hospital
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

- -

Oct 09, 2019
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 25, 2018
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3,PP4. -

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

- -

Jan 19, 2017
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 01, 2019
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: literature only

PS3: Low/absent in vivo enzymatic activity in homozygote. PS3: Low in vitro enzymatic activity. PM2: Very low frequency in GnomAD -

not provided Pathogenic:4
Dec 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

SGSH: PM3:Very Strong, PM2, PM5, PP3, PS3:Supporting -

Mar 07, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published functional studies demonstrate very low sulfamidase production compared to wild-type (Perkins et al., 1999).; 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: 18407553, 24816101, 11668611, 21061399, 31236806, 28963436, 30809705, 30548430, 10601282, 18392742, 15146460, 11793481, 22976768, 26787381, 21671382, 29023963, 28844463, 9285796, 31718697, 31980526, 32036093, 34349725, 34426522, 31589614, 33726816) -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 02, 2016
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Abnormal circulating carbohydrate concentration Pathogenic:1
Jan 01, 2017
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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
0.96
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.95
D;.
Eigen
Pathogenic
0.89
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Pathogenic
0.64
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.8
H;.
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-7.6
D;.
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D;.
Sift4G
Pathogenic
0.0
D;.
Polyphen
1.0
D;.
Vest4
0.98
MVP
0.99
MPC
0.90
ClinPred
0.99
D
GERP RS
3.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.99

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.

Other links and lift over

dbSNP: rs104894636; hg19: chr17-78190860; API