17-80213815-C-T

Position:

chr17-80213815-C-T

Variant summary

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

The NM_000199.5(SGSH):c.734G>A(p.Arg245His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000518 in 1,602,690 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 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00053 ( 0 hom. )

Consequence

SGSH
NM_000199.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:26O:1

Conservation

PhyloP100: 7.36

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:

SGSH (HGNC:):

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, 0.865

PP5

Variant 17-80213815-C-T is Pathogenic according to our data. Variant chr17-80213815-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 5107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80213815-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGSH	NM_000199.5 linkuse as main transcript	c.734G>A	p.Arg245His	missense_variant	6/8	ENST00000326317.11	NP_000190.1	P51688

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGSH	ENST00000326317.11 linkuse as main transcript	c.734G>A	p.Arg245His	missense_variant	6/8	1	NM_000199.5	ENSP00000314606.6		P51688

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

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:

0.000808

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000328

AC:

AN:

228912

Hom.:

AF XY:

0.000322

AC XY:

AN XY:

124192

show subpopulations

Gnomad AFR exome

AF:

0.000138

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000583

Gnomad SAS exome

AF:

0.0000704

Gnomad FIN exome

AF:

0.0000565

Gnomad NFE exome

AF:

0.000667

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000532

AC:

771

AN:

1450328

Hom.:

Cov.:

AF XY:

0.000538

AC XY:

388

AN XY:

720716

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.0000232

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000509

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000677

Gnomad4 OTH exome

AF:

0.000217

GnomAD4 genome

AF:

0.000387

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.0000962

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:

0.000808

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000533

Hom.:

Bravo

AF:

0.000336

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000307

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:26Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-A

Pathogenic:16

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 11, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 245 of the SGSH protein (p.Arg245His). This variant is present in population databases (rs104894635, gnomAD 0.07%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IIIA (PMID: 9158154, 9700599, 15146460, 21061399, 22976768, 26331342). 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: 5107). 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 95%. Experimental studies have shown that this missense change affects SGSH function (PMID: 10601282). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_000199.3(SGSH):c.734G>A(R245H) is classified as pathogenic in the context of mucopolysaccharidosis type IIIA. Sources cited for classification include the following: PMID 22976788, 21061399, 26787381 and 10601282. Classification of NM_000199.3(SGSH):c.734G>A(R245H) 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jul 15, 2019	PS3, PS4, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 22, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The SGSH c.734G>A (p.Arg245His) variant is one of the most commonly detected variants in individuals with mucopolysaccharidosis type III, accounting for up to 58% of disease alleles in some European populations (Fedele et al. 2015). Across a selection of the available literature, the p.Arg245His variant has been identified in a homozygous state in 37 individuals, in a compound heterozygous state in 75 individuals, and in a heterozygous state in two individuals (Blanch et al. 1997; Weber et al. 1998; Meyer et al. 2008; Valstar et al. 2010; Wilkin et al. 2016). The variant was absent from 20 control alleles but is reported at a frequency of 0.00060 in the European (non-Finnish) population of the Exome Aggregation Consortium. The Arg245 residue is not conserved among human sulphatases. Functional studies showed that the p.Arg245His variant protein is expressed at a lower level than wild type, affects protein stability, and results in 83% of normal activity (Perkins et al. 1999; Sidhu et al. 2014). Based on the collective evidence, the p.Arg245His variant is classified as pathogenic for mucopolysaccharidosis type III. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	Mar 25, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The c.734G>A(p.Arg245His) missense variant in SGSH gene has been reported in individuals affected with mucopolysaccharidosis type IIIA (Wilkin et al., 2016). Experimental studies have shown that this missense change affects SGSH function (Perkins et al., 1999). This variant is reported with the allele frequency (0.03%) in the gnomAD and novel in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Arg at position 245 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	literature only	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Jan 01, 2019	PS3: Low/absent in vivo enzymatic activity in homozygote; Low in vitro enzymatic activity. PS4: The prevalence of the variant in affected individuals is significantly increase compared with the prevalence in controls. PM2: Absent from GnomAD -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not provided

Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	SGSH: PM3:Very Strong, PM2, PM5 -
Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 19, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 29, 2021	Published functional studies found R245H is associated with significantly reduced sulfamidase activity (Perkins et al., 1999); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 18407553, 11182930, 25807448, 19383612, 21671382, 21061399, 10601282, 26331342, 9285796, 9158154, 24816101, 26787381, 27590925, 21228398, 31718697, 31980526, 32036093, 31589614, 12490062, 31031587, 33726816, 29023963) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 24, 2017	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2014

- -

SGSH-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2024

The SGSH c.734G>A variant is predicted to result in the amino acid substitution p.Arg245His. This variant was documented to be pathogenic for Sanfilippo syndrome type A (Blanch et al. 1997. PubMed ID: 9158154; Nijmeijer et al. 2019. PubMed ID: 31718697; Ugrinov et al. 2015. PubMed ID: 25807448). At PreventionGenetics, we have also previously identified this variant in affected patients. This variant is reported in 0.065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Neurodegeneration

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Institute of Human Genetics, University of Wuerzburg

- -

Sanfilippo syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jun 26, 2016

Variant summary: The SGSH c.734G>A (p.Arg245His) variant causes a missense change involving a conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 30/72670 (1/2422), which does not exceed the estimated maximal expected allele frequency for a pathogenic SGSH variant of 1/309. The variant of interest has been reported in multiple affected individuals as homozygotes and compound heterozygotes via publications. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic. -

Mucopolysaccharidosis

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.077

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Benign

0.96

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.29

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.87

Sift4G

Benign

0.25

Vest4

0.80

MVP

0.83

ClinPred

0.45

GERP RS

4.5

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