rs104894639

chr17-80210622-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000199.5(SGSH):c.1339G>A(p.Glu447Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000236 in 1,613,584 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. E447G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: SGSH NM_000199.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 5.95

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 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-80210621-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2918842.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 17-80210622-C-T is Pathogenic according to our data. Variant chr17-80210622-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80210622-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGSH	NM_000199.5	c.1339G>A	p.Glu447Lys	missense_variant	8/8	ENST00000326317.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGSH	ENST00000326317.11	c.1339G>A	p.Glu447Lys	missense_variant	8/8	1	NM_000199.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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

GnomAD3 exomes AF: 0.0000681 AC: 17 AN: 249718 Hom.: 0 AF XY: 0.0000591 AC XY: 8 AN XY: 135466

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000348

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: 0.0000356

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461414 Hom.: 0 Cov.: 35 AF XY: 0.0000193 AC XY: 14 AN XY: 727022

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152170 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74318

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

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

Alfa AF: 0.0000557 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-A Pathogenic:10

Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	May 24, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 447 of the SGSH protein (p.Glu447Lys). This variant is present in population databases (rs104894639, gnomAD 0.04%). This missense change has been observed in individual(s) with mucopolysaccharidosis (MPS) type IIIA (PMID: 9158154, 19099774, 26787381; 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: 5114). 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%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Homozygote Missense variant c.1339G>A in Exon 8 of the SGSH gene that results in the amino acid substitution p.Glu447Lys was identified. The observed variant has a maximum allele frequency of 0.00007/0.00003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic and LikelyPathogenic (Variant ID: 5114). This variant was reported among patients affected by mucopolysaccharidosis (Zanetti A et al, 2010). Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	-	The homozygous missense variation in exon 8 of SGSH gene that results in the amino acid substitution to lysine for glutamic acis at codon of 447 was detected. The variant c.1339G>A (p.Glu447Lys) has not been reported in 1000 genome and has a MAF of 0.007% in the gnomAD database. The insilico prediction of the variant is dIsease causing by MutationTaster, CADD , PROVEAN and SIFT. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The SGSH c.1339G>A (p.Glu447Lys) variant has been reported in three studies and is found in a total of five individuals with mucopolysaccharidosis including two in a homozygous state and three in a compound heterozygous state (including two siblings who carried a canonical splice site (donor) variant on the second allele) (Blanch et al. 1997; Chabas et al. 2001; Shapiro et al. 2016). The p.Glu447Lys variant was absent from 120 control alleles (Blanch et al. 1997) and is reported at a frequency of 0.00002 in the total population of the Exome Aggregation Consortium. Based on the evidence, the p.Glu447Lys variant is classified as likely pathogenic for mucopolysaccharidosis, type III. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
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 vivo enzymatic activity in homozygotes; PM2: Very low frequency in GnomAD -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 18, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 03, 2019	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 17, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2022	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: 18254660, 21228398, 25807448, 30809705, 11668611, 24347096, 24816101, 19099774, 11343308, 9158154) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2022

The c.1339G>A (p.E447K) alteration is located in exon 8 (coding exon 8) of the SGSH gene. This alteration results from a G to A substitution at nucleotide position 1339, causing the glutamic acid (E) at amino acid position 447 to be replaced by a lysine (K). Based on data from gnomAD, the A allele has an overall frequency of 0.01% (18/281098) total alleles studied. The highest observed frequency was 0.04% (13/35374) of Latino alleles. This alteration has been detected in the homozygous state and as compound heterozygous with other pathogenic SGSH alterations in multiple unrelated individuals with Sanfilippo syndrome (Chabas, 2001; Matalonga, 2014; Blanch, 1997; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, E447K is deleterious and moderately destabilizing to the local structure (Sidhu, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.97		Gain of methylation at E447 (P = 0.0131);
MVP		0.98
MPC		0.81
ClinPred		0.99	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.99

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: rs104894639; hg19: chr17-78184421; COSMIC: COSV58339170; COSMIC: COSV58339170;