rs104894638

Positions:

chr17-80214672-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_000199.5(SGSH):c.449G>A(p.Arg150Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,318 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 (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

SGSH
NM_000199.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.76

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 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.877

PP5

Variant 17-80214672-C-T is Pathogenic according to our data. Variant chr17-80214672-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80214672-C-T 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.449G>A	p.Arg150Gln	missense_variant	4/8	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.449G>A	p.Arg150Gln	missense_variant	4/8	1	NM_000199.5	ENSP00000314606	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152182

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

250524

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135752

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000342

AC:

AN:

1461136

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

726870

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000432

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74338

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000193

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

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:8

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 06, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 150 of the SGSH protein (p.Arg150Gln). This variant is present in population databases (rs104894638, gnomAD 0.005%). This missense change has been observed in individuals with mucopolysaccharidosis type III (PMID: 9401012, 9554748, 9744479, 11343308, 21061399, 21204211). ClinVar contains an entry for this variant (Variation ID: 5113). 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%. Experimental studies have shown that this missense change affects SGSH function (PMID: 10727844). This variant disrupts the p.Arg150 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been observed in individuals with SGSH-related conditions (PMID: 11182930, 21204211), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 17, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 19, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 04, 2018	Variant summary: SGSH c.449G>A (p.Arg150Gln) results in a conservative amino acid change located in the Sulfatase, N-terminal domain of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 276994 control chromosomes (gnomAD and publication data). c.449G>A has been reported in the literature as a homozygous and compound heterozygous allele in multiple individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (Bunge 1997, Di Natale 1998, Heron 2010, Valstar 2010). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on enzyme activity, showing that the variant results in <10% of normal activity (Esposito 2000). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

SGSH-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2024

The SGSH c.449G>A variant is predicted to result in the amino acid substitution p.Arg150Gln. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with mucopolysaccharidosis type IIIA (see for example, Bunge et al. 1997. PubMed ID: 9401012; Yogalingam and Hopwood. 2001. PubMed ID: 11668611; Valstar et al. 2010. PubMed ID: 21061399). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD. An in vitro experimental study suggests this variant abolishes enzyme activity (Esposito et al. 2000. PubMed ID: 10727844). Alternate missense substitutions affecting the same amino acid (p.Arg150Trp and p.Arg150Gly) have been reported in multiple individuals with mucopolysaccharidosis type IIIA (Beesley et al. 2000. PubMed ID: 11182930; Table S2, Héron et al. 2011. PubMed ID: 21204211). Given the evidence, the c.449G>A (p.Arg150Gln) variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.33

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.88

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

A;A;A

Sift4G

Uncertain

0.025

Vest4

0.84

MVP

0.77

ClinPred

0.87

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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