17-80213846-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM5PP3_StrongPP5_Very_Strong

The NM_000199.5(SGSH):c.703G>A(p.Asp235Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,608,590 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. D235H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SGSH
NM_000199.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.40

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

familial pityriasis rubra pilaris
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
psoriasis 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

CARD14 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-80213846-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2817814.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 17-80213846-C-T is Pathogenic according to our data. Variant chr17-80213846-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 553004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGSH	NM_000199.5 link	c.703G>A	p.Asp235Asn	missense_variant	Exon 6 of 8	ENST00000326317.11	NP_000190.1	P51688

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGSH	ENST00000326317.11 link	c.703G>A	p.Asp235Asn	missense_variant	Exon 6 of 8	1	NM_000199.5	ENSP00000314606.6		P51688

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000478

GnomAD2 exomes

AF:

0.0000168

AC:

AN:

237402

AF XY:

0.0000232

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000296

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000168

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000124

AC:

AN:

1456364

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

724286

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33466

American (AMR)

AF:

0.0000226

AC:

AN:

44312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25906

East Asian (EAS)

AF:

0.000126

AC:

AN:

39550

South Asian (SAS)

AF:

0.00

AC:

AN:

85346

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00000990

AC:

AN:

1111290

Other (OTH)

AF:

0.00

AC:

AN:

60184

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41464

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000815

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.00000828

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

May 11, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SGSH c.703G>A (p.Asp235Asn) results in a conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 237402 control chromosomes (gnomAD). c.703G>A has been reported in the literature in compound heterozygous individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (Beesley_2000, Lee-Chen_2002, Heron_2011). These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon (Asp235Val) has been reported in affected individuals, suggesting this may be an important residue (Beesley_2000). One publication reports that the variant protein has 1.7% N-Sulphatase activity (Lee-Chen_2002). Three ClinVar submitters have assessed the variant since 2014: two classify the variant as likely pathogenic and one as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 07, 2021

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 21, 2024

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A homozygous variation in exon 6 of the SGSH gene that results in the amino acid substitution of Asparagine for Aspartic acid at codon 235 was detected. The observed variant c.703G>A (p.Asp235Asn) has not been reported in the 1000 genomes and has a MAF of 0.0017% in the gnomAD database. The in-silico prediction of the variant is disease causing by Mutation Taster, PolyPhen2, DANN and Polyphen2. In summary, the variant meets our criteria to be classified as pathogenic. -

Jul 27, 2017

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

May 14, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 30, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 235 of the SGSH protein (p.Asp235Asn). This variant is present in population databases (rs753472891, gnomAD 0.02%). This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 11182930, 12000360, 19099774; internal data). ClinVar contains an entry for this variant (Variation ID: 553004). 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: 12000360). This variant disrupts the p.Asp235 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been observed in individuals with SGSH-related conditions (PMID: 9401012), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

SGSH-related disorder

Pathogenic:1

Oct 13, 2022

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SGSH c.703G>A variant is predicted to result in the amino acid substitution p.Asp235Asn. This variant along with a second variant in SGSH was reported in multiple individuals with Sanfilippo syndrome IIIA (also known as Sanfilippo A) (Beesley et al. 2000. PubMed ID: 11182930; Zhang et al. 2008. PubMed ID: 19099774; Lee-Chen et al. 2002. PubMed ID: 12000360; Table S2, Héron et al. 2011. PubMed ID: 21204211; Delgadillo et al. 2013. PubMed ID: 24314109). In addition, a different variant affecting the same amino acid (p.Asp235Val) was reported to be pathogenic for Sanfilippo syndrome A (Bunge et al. 1997. PubMed ID: 9401012). Structure and computational predication studies suggest this variant disrupts enzyme activity (Sidhu et al. 2014. PubMed ID: 24816101; Ugrinov et al. 2015. PubMed ID: 25807448). This variant is reported in 0.015% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-78187645-C-T). This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Apr 03, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect (Western blot analysis revealed that precursor and mature protein were expressed at significantly lower levels and residual enzyme activity was 1.7% of controls) (PMID: 12000360); 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: 31589614, 25807448, 24816101, 11182930, 12000360, 36972941, 35629088) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.79

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.4

PhyloP100

7.4

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.047

Polyphen

1.0

Vest4

0.88

MutPred

0.87

Gain of loop (P = 0.0312);

MVP

0.98

MPC

0.75

ClinPred

0.91

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.92

Mutation Taster

=14/86

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over