rs138504221

Positions:

chr17-80212128-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The ENST00000326317.11(SGSH):c.892T>C(p.Ser298Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000179 in 1,613,568 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 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

SGSH
ENST00000326317.11 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:24O:1

Conservation

PhyloP100: 9.02

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:

CARD14 (HGNC:16446): (caspase recruitment domain family member 14) This gene encodes a caspase recruitment domain-containing protein that is a member of the membrane-associated guanylate kinase (MAGUK) family of proteins. Members of this protein family are scaffold proteins that are involved in a diverse array of cellular processes including cellular adhesion, signal transduction and cell polarity control. This protein has been shown to specifically interact with BCL10, a protein known to function as a positive regulator of cell apoptosis and NF-kappaB activation. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2012]

CARD14 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000326317.11

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.861

PP5

Variant 17-80212128-A-G is Pathogenic according to our data. Variant chr17-80212128-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 30459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80212128-A-G 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.892T>C	p.Ser298Pro	missense_variant	7/8	ENST00000326317.11	NP_000190.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGSH	ENST00000326317.11 linkuse as main transcript	c.892T>C	p.Ser298Pro	missense_variant	7/8	1	NM_000199.5	ENSP00000314606	P1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152148

Hom.:

Cov.:

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000958

AC:

AN:

250638

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135796

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:

0.000212

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000182

AC:

266

AN:

1461302

Hom.:

Cov.:

AF XY:

0.000182

AC XY:

132

AN XY:

726938

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:

0.00

Gnomad4 NFE exome

AF:

0.000237

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000151

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0000481

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:

0.000309

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000250

Hom.:

Bravo

AF:

0.000128

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-A

Pathogenic:15

Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Dec 10, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 298 of the SGSH protein (p.Ser298Pro). This variant is present in population databases (rs138504221, gnomAD 0.02%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IIIA (PMID: 9401012, 18407553, 21671382, 22976768, 29023963). ClinVar contains an entry for this variant (Variation ID: 30459). 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. Experimental studies have shown that this missense change affects SGSH function (PMID: 21671382). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	Apr 09, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 02, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 04, 2022	PS3, PM2, PM3_Very Strong -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant has been previously reported as a homozygous variant or a heterozygous variant in combination with another pathogenic variant in SGSH in several individuals with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (PMID: 9401012, 18407553, 21671382, 22976768, 29023963). Functional studies have demonstrated that this variant affects the folding and stability of the SGSH protein, resulting in reduced enzymatic activity (PMID: 21671382). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.011% (30/282024) and thus is presumed to be rare. The c.892T>C (p.Ser298Pro) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.892T>C (p.Ser298Pro) variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Apr 30, 2020	This variant has been previously reported as disease-causing PMIDs 21671382, 29023963, 9401012, 24816101, 25807448. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The SGSH c.892T>C (p.Ser298Pro) variant has been reported in four studies and is found in a total of 51 individuals with mucopolysaccharidosis, type III including four in a homozygous state, 45 in a compound heterozygous state, and two in a heterozygous state in whom a second variant was not identified (Bunge et al. 1997; Meyer et al. 2008; Valstar et al. 2010; Shapiro et al. 2016). Individuals carrying the p.Ser298Pro variant demonstrate a milder phenotype (Meyer et al. 2008; Valstar et al. 2010). The p.Ser298Pro variant was absent from 100 controls but is reported at a frequency of 0.00017 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in BHK cells transfected with the p.Ser298Pro variant demonstrated the variant results in reduced protein stability compared to wild type as well as low residual sulfamidase activity (Muschol et al. 2011). Based on the collective evidence, the p.Ser298Pro 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. -

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 23, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 27, 2023	PP3, PM2_moderate, PM3_strong, PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	Published functional studies demonstrate an effect on folding and stability of the sulfamidase enzyme, resulting in significantly reduced enzymatic activity (Muschol et al., 2011) 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: 31980526, 31536183, 32581362, 31718697, 29023963, 28451919, 24524415, 21204211, 24271936, 21061399, 15146460, 22976768, 24816101, 26787381, 18407553, 25807448, 9401012, 21671382) -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Diarrhea;C0028738:Nystagmus;C0557874:Global developmental delay;C0854723:Retinal dystrophy;C1301509:Severely reduced visual acuity;C1836830:Developmental regression;C1836923:Gastrointestinal dysmotility

Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

- -

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

Aug 02, 2017

Variant summary: The SGSH c.892T>C (p.Ser298Pro) variant involves the alteration of a conserved nucleotide that lies within the Alkaline-phosphatase-like, core domain, Sulfatase, N-terminal domain, and Alkaline phosphatase-like, alpha/beta/alpha domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Functional studies found no to minimal (2.3% of wild-type) heparin-N sulfatase activity associated with this variant (Pollard_JIMD_2013, Muschol_AJMG_2011). This variant was found in the large control database ExAC and in the literature at a frequency of 0.0000917 (11/120004 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic SGSH variant (0.0032275). The variant has been found in numerous MPS IIIA patients, in compound heterozygotes as well as homozygotes, and was reported as being associated with a clinically mild phenotype (Valstar_Mutat_Annals of Neurology_2010, Meyer_HM_2008). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant 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

0.86

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

D;D

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.92

D;D

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Benign

1.5

L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.9

D;.

REVEL

Pathogenic

0.88

Sift

Uncertain

0.017

D;.

Sift4G

Benign

0.18

T;D

Polyphen

1.0

D;.

Vest4

0.95

MVP

0.99

MPC

0.86

ClinPred

0.61

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.96

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