chr17-80217060-C-T

Position:

chr17-80217060-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong

The ENST00000326317.11(SGSH):c.221G>A(p.Arg74His) variant causes a missense change. The variant allele was found at a frequency of 0.0000044 in 1,590,362 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. R74L) has been classified as Pathogenic.

Frequency

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

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

SGSH
ENST00000326317.11 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.14

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 15 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000326317.11

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-80217061-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.837

PP5

Variant 17-80217060-C-T is Pathogenic according to our data. Variant chr17-80217060-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGSH	NM_000199.5 linkuse as main transcript	c.221G>A	p.Arg74His	missense_variant	2/8	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.221G>A	p.Arg74His	missense_variant	2/8	1	NM_000199.5	ENSP00000314606.6		P51688

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000417

AC:

AN:

1437992

Hom.:

Cov.:

AF XY:

0.00000420

AC XY:

AN XY:

713484

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000489

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:

0.00000363

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152370

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000837

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-A

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 17, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Jul 22, 2023	The observed missense c.221G>Ap.Arg74His variant in SGSH gene has been reported previously in homozygous or compound heterozygous state in individuals affected with Mucopolysaccharidoses MPS Zanetti et al., 2019. This variant is reported with the allele frequency of 0.0004% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic / Likely Pathogenic multiple submissions. The amino acid Arg at position 74 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg74His in SGSH is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence Polyphen - Damaging, SIFT - Damaging, and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. For these reasons, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 74 of the SGSH protein (p.Arg74His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with MPS IIIA (PMID: 9401012, 11343308; Invitae). 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: 550504). 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%. This variant disrupts the p.Arg74 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9285796, 9401012, 11343308, 22976768, 28844463). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 03, 2021	Variant summary: SGSH c.221G>A (p.Arg74His) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. 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 4.7e-06 in 211504 control chromosomes (gnomAD and publication data). c.221G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A), including at least two homozygotes (Bunge_1997, Chabas_2001, Montfort_2004). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports this variant results in reducing sulfamidase activity compared to WT activity (Montfort_2004). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=1) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely pathogenic, criteria provided, single submitter	literature only	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Jan 01, 2019	PS3: Low in vitro enzymatic activity. PM2: Absent from GnomAD -

SGSH-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 17, 2024

The SGSH c.221G>A variant is predicted to result in the amino acid substitution p.Arg74His. This variant, also referred to as R74H, has been reported in the homozygous state in several individuals with a diagnosis or clinical features suggestive of mucopolysaccharidosis type IIIA (MPS IIIA), also known as Sanfilippo syndrome A (Bunge et al. 1997. PubMed ID: 9401012; Chabás et al. 2001. PubMed ID: 11343308; Gul et al. 2023. PubMed ID: 37772257). It was also reported along with a second pathogenic SGSH variant in a patient with MPS IIIA (Chabás et al. 2001. PubMed ID: 11343308). A different missense change impacting the same amino acid (c.220C>T; p.Arg74Cys) has been reported in individuals with MPS IIIA (Weber et al. 1997. PubMed ID: 9285796; Yassaee et al. 2017. PubMed ID: 28844463). This amino acid residue is highly conserved and is a critical component to the protein's active site; changes to this amino acid result in decreased enzyme stability and disruption of ion binding (Sidhu et al. 2014. PubMed ID: 24816101). This variant is reported in 0.0037% of alleles in individuals of South Asian descent in gnomAD; however, the quality of this data is questionable and should be treated with caution. This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 21, 2023

Published functional studies demonstrate that the variant results in significantly decreased enzyme activity (PMID: 15542396); Not observed at significant frequency in large population cohorts (gnomAD); 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: 24816101, 16174644, 9401012, 15542396) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.79

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.25

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.84

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

D;D;N

Sift4G

Benign

0.46

Vest4

0.69

MVP

0.90

ClinPred

1.0

GERP RS

2.7

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