17-80210831-C-T

Position:

chr17-80210831-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000199.5(SGSH):c.1130G>A(p.Arg377His) variant causes a missense change. The variant allele was found at a frequency of 0.0000161 in 1,613,840 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R377C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

SGSH
NM_000199.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 6.03

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 18 ACMG points.

PM1

In a strand (size 8) in uniprot entity SPHM_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_000199.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-80210832-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 17-80210831-C-T is Pathogenic according to our data. Variant chr17-80210831-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1297691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80210831-C-T is described in Lovd as [Pathogenic]. Variant chr17-80210831-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGSH	NM_000199.5 linkuse as main transcript	c.1130G>A	p.Arg377His	missense_variant	8/8	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.1130G>A	p.Arg377His	missense_variant	8/8	1	NM_000199.5	ENSP00000314606	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

250948

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135810

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461668

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727122

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-A

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 16, 2022	Variant summary: SGSH c.1130G>A (p.Arg377His) results in a non-conservative amino acid change in the encoded protein sequence. This variant is predicted to impact the structure of the SGSH protein due to loss of a buried salt bridge with Asp 477 and of hydrogen bonds to Ser 366 and Met 376 (Sidhu_2014). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250948 control chromosomes. c.1130G>A has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (example, Bunge_1997, Valstar_2010, Knottnerus_2017, Nijmeijer_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 377 of the SGSH protein (p.Arg377His). This variant is present in population databases (rs746037899, gnomAD 0.003%). This missense change has been observed in individual(s) with mucopolysaccharidosis IIIA (PMID: 29023963, 31718697). ClinVar contains an entry for this variant (Variation ID: 1297691). 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 80%. This variant disrupts the p.Arg377 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9554748, 12000360, 19099774, 21910976). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 16, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Aug 08, 2022	A compound heterozygous missense variation in exon 8 and exon 7 of the SGSH gene that results in the amino acid substitution of Histidine for Arginine at codon377 was detected. The observed variant c.1130G>A(p.Arg377His) has a minor allele frequency of 0.0003%, and 0.0008% in the 1000 genomes and gnomAD databases. Alternative variant chr17:78184631 G⇒A (Arg377Cys) is classified Pathogenic by UniProt Variants (and confirmed using ACMG). The in silico prediction of the variant is benign by DANN, SIFT, LRT ,FATHMM-XF, MutPred and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 08, 2024	- -

not provided

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

SGSH-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 30, 2024

The SGSH c.1130G>A variant is predicted to result in the amino acid substitution p.Arg377His. This variant has been reported with a second SGSH variant in individuals with mucopolysaccharidosis type IIIA (see, for example, Weber et al. 1997. PubMed ID: 9285796; Valstar et al. 2010. PubMed ID: 21061399; Nijmeijer et al. 2019. PubMed ID: 31718697; Table 2, Knottnerus et al. 2017. PubMed ID: 29023963). Other amino acid changes at this position (p.Arg377Cys, p.Arg377Ser, p.Arg377Leu) have also been reported in individuals with mucopolysaccharidosis type IIIA (Di Natale et al. 1998. PubMed ID: 9554748; Sudrié-Arnaud et al. 2021. PubMed ID: 33673364; Pollard et al. 2013. PubMed ID: 22976768). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.48

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.52

MutationAssessor

Pathogenic

3.0

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-4.5

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.93

MutPred

0.98

Loss of sheet (P = 0.0181);

MVP

0.92

MPC

0.86

ClinPred

1.0

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.78

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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