rs766938111

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

Scores

8
7
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:1

Conservation

PhyloP100: 6.03
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]
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
SGSHNM_000199.5 linkuse as main transcriptc.1063G>A p.Glu355Lys missense_variant 8/8 ENST00000326317.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SGSHENST00000326317.11 linkuse as main transcriptc.1063G>A p.Glu355Lys missense_variant 8/81 NM_000199.5 P1

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152178
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000282
AC:
7
AN:
248350
Hom.:
0
AF XY:
0.00000743
AC XY:
1
AN XY:
134598
show subpopulations
Gnomad AFR exome
AF:
0.0000621
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000888
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000219
AC:
32
AN:
1459288
Hom.:
0
Cov.:
34
AF XY:
0.0000165
AC XY:
12
AN XY:
725914
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.0000196
Gnomad4 NFE exome
AF:
0.0000225
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152178
Hom.:
0
Cov.:
33
AF XY:
0.0000404
AC XY:
3
AN XY:
74328
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000331
Hom.:
0
Bravo
AF:
0.0000453
ExAC
AF:
0.0000330
AC:
4
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

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 providedclinical testingCounsylDec 07, 2018- -
Likely pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 26, 2023Variant 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 submitterclinical testingGeisinger Autism and Developmental Medicine Institute, Geisinger Health SystemApr 26, 2017The 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 submitterclinical testingBaylor GeneticsMar 20, 2024- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 22, 2023This 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 submitterclinical testingIllumina Laboratory Services, IlluminaMay 07, 2018The 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 submitterclinical testingGenome-Nilou LabNov 07, 2021- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxAug 11, 2022In 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.32
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.48
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.38
T
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D
M_CAP
Pathogenic
0.74
D
MetaRNN
Pathogenic
0.80
D
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Uncertain
2.0
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.53
T
PROVEAN
Uncertain
-3.3
D
REVEL
Pathogenic
0.87
Sift
Uncertain
0.0030
D
Sift4G
Benign
0.063
T
Polyphen
1.0
D
Vest4
0.47
MVP
0.98
MPC
0.71
ClinPred
0.65
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.78
gMVP
0.92

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.

Other links and lift over

dbSNP: rs766938111; hg19: chr17-78184697; API