rs138504221

chr17-80212128-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000199.5(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 NM_000199.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:22 O:1
• Conservation: PhyloP100: 9.02

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 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 NM_000199.5
• 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	UniProt
SGSH	NM_000199.5	c.892T>C	p.Ser298Pro	missense_variant	7/8	ENST00000326317.11

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152148 Hom.: 0 Cov.: 32

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: 24 AN: 250638 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135796

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.: 0 Cov.: 31 AF XY: 0.000182 AC XY: 132 AN XY: 726938

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: 23 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74452

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.: 0

Bravo AF: 0.000128

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-A Pathogenic:14

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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 02, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Dec 10, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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	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	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 04, 2022	PS3, PM2, PM3_Very Strong -
Pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2010	- -
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. -

not provided Pathogenic:5

Likely 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	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)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 23, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	- -

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

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.61	T
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	D
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

Other links and lift over

dbSNP: rs138504221; hg19: chr17-78185927;