17-80213815-C-T

Variant names:

• chr17-80213815-C-T
• rs104894635
• NM_000199.5:c.734G>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:27 O:1
• Conservation: PhyloP100: 7.36

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]

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]

ACMG classification

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 rank	MANE	Protein	UniProt
SGSH	NM_000199.5	c.734G>A	p.Arg245His	missense_variant	Exon 6 of 8	ENST00000326317.11	NP_000190.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGSH	ENST00000326317.11	c.734G>A	p.Arg245His	missense_variant	Exon 6 of 8	1	NM_000199.5	ENSP00000314606.6

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152244 Hom.: 0 Cov.: 32

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: 75 AN: 228912 Hom.: 0 AF XY: 0.000322 AC XY: 40 AN XY: 124192

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.: 0 Cov.: 31 AF XY: 0.000538 AC XY: 388 AN XY: 720716

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: 59 AN: 152362 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74508

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.: 0

Bravo AF: 0.000336

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000307 AC: 37

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:27 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-A Pathogenic:17

Mar 25, 2021

Centre for Inherited Metabolic Diseases, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 20, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 22, 2023

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

- -

-

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 02, 2024

Fulgent Genetics, Fulgent 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

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 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 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). 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). For these reasons, this variant has been classified as Pathogenic. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 11, 2022

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

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

- -

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/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 -

Jul 15, 2019

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4, PP3 -

not provided Pathogenic:6

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, PM5 -

Apr 19, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 01, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 24, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 29, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Inborn genetic diseases Pathogenic:1

Sep 07, 2014

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SGSH-related disorder Pathogenic:1

May 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

-

Institute of Human Genetics, University of Wuerzburg

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sanfilippo syndrome Pathogenic:1

Jun 26, 2016

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.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

-

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	0.85
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	29
DANN	Benign	0.96
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.29	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.87	D
Sift4G	Benign	0.25	T
Vest4		0.80
MVP		0.83
ClinPred		0.45	T
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

Other links and lift over

dbSNP: rs104894635; hg19: chr17-78187614;