The variant chr17-78188504-G-A, SGSH(NM_000199.5):c.416C>T,p.(Thr139Met) was identified in an individual with NDD. Inheritance was not applicable (heterozygous). The variant was reviewed according to current ACMG recommendations and classified as Likely Pathogenic (criteria: PM2_Supporting, PM3_Strong, PP3_Supporting, PP4_Supporting). This variant was identified in a compound heterozygous state with the variantNM_000199.5(SGSH):c.267C>A (p.Tyr89Ter) ( Variation ID: 983123).
ClinVar Genomic variation as it relates to human health
NM_000199.5(SGSH):c.416C>T (p.Thr139Met)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(7)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Conflicting classifications of pathogenicity
Likely pathogenic(3); Uncertain significance(3)
Likely pathogenic(3); Uncertain significance(3)
7
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000199.5(SGSH):c.416C>T (p.Thr139Met)
Variation ID: 551670 Accession: VCV000551670.15
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q25.3 17: 80214705 (GRCh38) [ NCBI UCSC ] 17: 78188504 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 5, 2018 Jun 17, 2024 Feb 8, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000199.5:c.416C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000190.1:p.Thr139Met missense NM_001352921.3:c.416C>T NP_001339850.1:p.Thr139Met missense NM_001352922.2:c.416C>T NP_001339851.1:p.Thr139Met missense NR_148201.2:n.330C>T non-coding transcript variant NC_000017.11:g.80214705G>A NC_000017.10:g.78188504G>A NG_008229.1:g.10696C>T - Protein change
- T139M
- Other names
- -
- Canonical SPDI
- NC_000017.11:80214704:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| SGSH | - | - |
GRCh38 GRCh38 GRCh37 |
997 | 1479 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
|
Feb 8, 2024 | RCV000666794.17 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Feb 25, 2021 | RCV001293360.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Feb 25, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual disability
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001481815.1
First in ClinVar: Feb 28, 2021 Last updated: Feb 28, 2021 |
Comment:
The variant chr17-78188504-G-A, SGSH(NM_000199.5):c.416C>T,p.(Thr139Met) was identified in an individual with NDD. Inheritance was not applicable (heterozygous). The variant was reviewed according to current ACMG recommendations … (more)
The variant chr17-78188504-G-A, SGSH(NM_000199.5):c.416C>T,p.(Thr139Met) was identified in an individual with NDD. Inheritance was not applicable (heterozygous). The variant was reviewed according to current ACMG recommendations and classified as Likely Pathogenic (criteria: PM2_Supporting, PM3_Strong, PP3_Supporting, PP4_Supporting). This variant was identified in a compound heterozygous state with the variantNM_000199.5(SGSH):c.267C>A (p.Tyr89Ter) ( Variation ID: 983123). (less)
|
|
|
Likely pathogenic
(Nov 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-III-A
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002045105.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
|
|
|
Uncertain significance
(Nov 12, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-III-A
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV002060236.2
First in ClinVar: Jan 15, 2022 Last updated: Nov 29, 2022 |
Comment:
NM_000199.3(SGSH):c.416C>T(T139M) is a missense variant classified as a variant of uncertain significance in the context of mucopolysaccharidosis type IIIA. T139M has been observed in cases … (more)
NM_000199.3(SGSH):c.416C>T(T139M) is a missense variant classified as a variant of uncertain significance in the context of mucopolysaccharidosis type IIIA. T139M has been observed in cases with relevant disease (PMID: 9285796; 24576347). Functional assessments of this variant are not available in the literature. T139M has been observed in population frequency databases (gnomAD: AFR 0.01%). In summary, there is insufficient evidence to classify NM_000199.3(SGSH):c.416C>T(T139M) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. (less)
|
|
|
Uncertain significance
(Sep 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-III-A
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003443328.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 139 of the SGSH protein (p.Thr139Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 139 of the SGSH protein (p.Thr139Met). This variant is present in population databases (rs775112689, gnomAD 0.004%). This missense change has been observed in individual(s) with Sanfilippo syndrome (PMID: 9285796, 24576347). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 551670). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-III-A
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004100649.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
The missense variant p.T139M in SGSH (NM_000199.5) has been submitted previously to ClinVar with conflicting interpretations of pathogenicity (Likely Pathogenic/ Uncertain Significance). No details for … (more)
The missense variant p.T139M in SGSH (NM_000199.5) has been submitted previously to ClinVar with conflicting interpretations of pathogenicity (Likely Pathogenic/ Uncertain Significance). No details for independent assesment are available for the Likely Pathogenic classification. It has not been reported previously in affected individuals to the best of our knowledge. The p.T139M variant is observed in 1/16,194 (0.0062%) alleles from individuals of African background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.The p.T139M missense variant is predicted to be damaging by both SIFT and PolyPhen2. The threonine residue at codon 139 of SGSH is conserved in all mammalian species. The nucleotide c.416 in SGSH is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. (less)
Clinical Features:
Aggressive behavior (present) , Abnormal facial shape (present) , Hyperactivity (present)
|
|
|
Likely pathogenic
(Feb 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-III-A
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004201089.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Aug 01, 2019)
|
no assertion criteria provided
Method: research
|
Mucopolysaccharidosis, MPS-III-A
Affected status: yes
Allele origin:
germline
|
Section for Clinical Neurogenetics, University of Tübingen
Accession: SCV001156105.1
First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020 |
|
Comment:
Comment:
NM_000199.3(SGSH):c.416C>T(T139M) is a missense variant classified as a variant of uncertain significance in the context of mucopolysaccharidosis type IIIA. T139M has been observed in cases with relevant disease (PMID: 9285796; 24576347). Functional assessments of this variant are not available in the literature. T139M has been observed in population frequency databases (gnomAD: AFR 0.01%). In summary, there is insufficient evidence to classify NM_000199.3(SGSH):c.416C>T(T139M) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 139 of the SGSH protein (p.Thr139Met). This variant is present in population databases (rs775112689, gnomAD 0.004%). This missense change has been observed in individual(s) with Sanfilippo syndrome (PMID: 9285796, 24576347). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 551670). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
The missense variant p.T139M in SGSH (NM_000199.5) has been submitted previously to ClinVar with conflicting interpretations of pathogenicity (Likely Pathogenic/ Uncertain Significance). No details for independent assesment are available for the Likely Pathogenic classification. It has not been reported previously in affected individuals to the best of our knowledge. The p.T139M variant is observed in 1/16,194 (0.0062%) alleles from individuals of African background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.The p.T139M missense variant is predicted to be damaging by both SIFT and PolyPhen2. The threonine residue at codon 139 of SGSH is conserved in all mammalian species. The nucleotide c.416 in SGSH is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The variant chr17-78188504-G-A, SGSH(NM_000199.5):c.416C>T,p.(Thr139Met) was identified in an individual with NDD. Inheritance was not applicable (heterozygous). The variant was reviewed according to current ACMG recommendations and classified as Likely Pathogenic (criteria: PM2_Supporting, PM3_Strong, PP3_Supporting, PP4_Supporting). This variant was identified in a compound heterozygous state with the variantNM_000199.5(SGSH):c.267C>A (p.Tyr89Ter) ( Variation ID: 983123).
Comment:
NM_000199.3(SGSH):c.416C>T(T139M) is a missense variant classified as a variant of uncertain significance in the context of mucopolysaccharidosis type IIIA. T139M has been observed in cases with relevant disease (PMID: 9285796; 24576347). Functional assessments of this variant are not available in the literature. T139M has been observed in population frequency databases (gnomAD: AFR 0.01%). In summary, there is insufficient evidence to classify NM_000199.3(SGSH):c.416C>T(T139M) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 139 of the SGSH protein (p.Thr139Met). This variant is present in population databases (rs775112689, gnomAD 0.004%). This missense change has been observed in individual(s) with Sanfilippo syndrome (PMID: 9285796, 24576347). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 551670). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
The missense variant p.T139M in SGSH (NM_000199.5) has been submitted previously to ClinVar with conflicting interpretations of pathogenicity (Likely Pathogenic/ Uncertain Significance). No details for independent assesment are available for the Likely Pathogenic classification. It has not been reported previously in affected individuals to the best of our knowledge. The p.T139M variant is observed in 1/16,194 (0.0062%) alleles from individuals of African background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.The p.T139M missense variant is predicted to be damaging by both SIFT and PolyPhen2. The threonine residue at codon 139 of SGSH is conserved in all mammalian species. The nucleotide c.416 in SGSH is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| First-line exome sequencing in Palestinian and Israeli Arabs with neurological disorders is efficient and facilitates disease gene discovery. | Hengel H | European journal of human genetics : EJHG | 2020 | PMID: 32214227 |
| Sanfilippo type A: new clinical manifestations and neuro-imaging findings in patients from the same family in Israel: a case report. | Sharkia R | Journal of medical case reports | 2014 | PMID: 24576347 |
| Novel mutations in Sanfilippo A syndrome: implications for enzyme function. | Weber B | Human molecular genetics | 1997 | PMID: 9285796 |
Text-mined citations for rs775112689 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.