chr17-80210898-C-T
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5
The NM_000199.5(SGSH):c.1063G>A(p.Glu355Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,611,466 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000022 ( 0 hom. )
Consequence
SGSH
NM_000199.5 missense
NM_000199.5 missense
Scores
8
7
4
Clinical Significance
Conservation
PhyloP100: 6.03
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000199.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.798
PP5
Variant 17-80210898-C-T is Pathogenic according to our data. Variant chr17-80210898-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 325835.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=4, Uncertain_significance=1}. Variant chr17-80210898-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| SGSH | NM_000199.5 | c.1063G>A | p.Glu355Lys | missense_variant | 8/8 | ENST00000326317.11 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SGSH | ENST00000326317.11 | c.1063G>A | p.Glu355Lys | missense_variant | 8/8 | 1 | NM_000199.5 | P1 |
Frequencies
GnomAD3 genomes 0.0000460 AC: 7AN: 152178Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000282 AC: 7AN: 248350Hom.: 0 AF XY: 0.00000743 AC XY: 1AN XY: 134598
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GnomAD4 exome AF: 0.0000219 AC: 32AN: 1459288Hom.: 0 Cov.: 34 AF XY: 0.0000165 AC XY: 12AN XY: 725914
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GnomAD4 genome 0.0000460 AC: 7AN: 152178Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74328
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:7Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Mucopolysaccharidosis, MPS-III-A Pathogenic:6Uncertain:1
| Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Dec 07, 2018 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 26, 2023 | Variant summary: SGSH c.1063G>A (p.Glu355Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 248350 control chromosomes. c.1063G>A has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (Beesley_2000, Sleat_2009, Nijmeijer_2019, Utz_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11182930, 31718697, 19383612, 25557439). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as pathogenic/likely pathogenic (n=5) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Geisinger Autism and Developmental Medicine Institute, Geisinger Health System | Apr 26, 2017 | The following ACMG criteria are met: PS3 (Well-established functional study), PM2 (Absent or very low frequency in population databases), PM3 (In trans with pathogenic variant, Beesley 2000), PP1 (Co-segregation with disease in multiple family members), PP3 (Multiple lines of computational evidence support deleterious effect). This variant has been reported previously in trans in a patient with confirmed MPS IIIA based on clinical features and enzyme activity. Two sisters in our clinical practice are compound heterozygotes for E355K and P225L and a clinical diagnosis of MPS IIIA was confirmed by clinical exam, positive urine screen, and absent enzyme activity in leukocytes. The younger sister has global developmental delays, autism spectrum disorder, sensorineural hearing loss, myopia, astigmatism, and a seizure disorder. The older sister has intellectual disability, autism spectrum disorder, sensorineural hearing loss, myopia, astigmatism, recurrent otitis media, precocious puberty, and seizure disorder. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 20, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 22, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 355 of the SGSH protein (p.Glu355Lys). This variant is present in population databases (rs766938111, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of mucopolysaccharidosis type III (PMID: 11182930, 19383612, 25557439, 31718697; 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: 325835). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SGSH protein function. For these reasons, this variant has been classified as Pathogenic. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 07, 2018 | The SGSH c.1063G>A (p.Glu355Lys) variant has been reported in a compound heterozygous state with a frameshift variant in one individual with mucopolysaccharidosis type 3 described as having very low or no detectable sulphamidase enzyme activity in leucocytes (Beesley et al. 2000). The p.Glu355Lys variant was also identified in a compound heterozygous state with a second missense variant in an individual with adult neuronal ceroid lipofuscinosis and absent protein (Sleat et al. 2009). The p.Glu355Lys variant was absent from 100 control chromosomes and is reported at a frequency of 0.00003 in the total population of the Exome Aggregation Consortium. Analysis of the crystal structure of glycosylated SGSH suggested that the p.Glu355Lys variant results in the loss of a surface salt bridge and hydrogen bonds (Sidhu et al. 2014). The p.Glu355Lys variant results in a non-conservative amino acid substitution, which occurs at a position that is conserved across species. The evidence for this variant is limited. The p.Glu355Lys variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity 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 | - - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 11, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25807448, 11668611, 31718697, 24816101, 11182930, 19383612, 21990111) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at