ClinVar Genomic variation as it relates to human health
NM_000199.5(SGSH):c.1027dup (p.Leu343fs)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000199.5(SGSH):c.1027dup (p.Leu343fs)
Variation ID: 198694 Accession: VCV000198694.21
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 17q25.3 17: 80210933-80210934 (GRCh38) [ NCBI UCSC ] 17: 78184732-78184733 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jun 28, 2015 Apr 20, 2024 Jan 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000199.5:c.1027dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000190.1:p.Leu343fs frameshift NM_000199.5:c.1027dupC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000199.3:c.1027dup NM_001352921.3:c.*114dup 3 prime UTR NM_001352922.2:c.*77dup 3 prime UTR NR_148201.2:n.941dup non-coding transcript variant NC_000017.11:g.80210935dup NC_000017.10:g.78184734dup NG_008229.1:g.14467dup NG_032778.1:g.45944dup LRG_1330:g.45944dup - Protein change
- L343fs
- Other names
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- Canonical SPDI
- NC_000017.11:80210933:GG:GGG
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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. |
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SGSH | - | - |
GRCh38 GRCh38 GRCh37 |
980 | 1458 |
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
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jan 17, 2024 | RCV000180105.12 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 14, 2023 | RCV000478433.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 2, 2017 | RCV000586132.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 26, 2019 | RCV001266816.4 |
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. |
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Pathogenic
(Feb 02, 2017)
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criteria provided, single submitter
Method: clinical testing
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Sanfilippo syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695955.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The SGSH c.1027dupC (p.Leu343Profs) variant results in a premature termination codon, predicted to cause a truncated or absent SGSH protein due to nonsense … (more)
Variant summary: The SGSH c.1027dupC (p.Leu343Profs) variant results in a premature termination codon, predicted to cause a truncated or absent SGSH protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 7/118674 control chromosomes at a frequency of 0.000059, which does not exceed the estimated maximal expected allele frequency of a pathogenic SGSH variant (0.0032275). This variant has been reported in multiple affected individuals as compund heterozygotes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Jun 03, 2014)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000232479.4
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Nov 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-III-A
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002045491.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
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Pathogenic
(Apr 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-III-A
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002813323.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Feb 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000568750.5
First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023 |
Comment:
Reported previously in association with mucopolysaccharidosis IIIA (MPS IIIA); however it is unclear if a second SGSH variant was identified (Weber et al., 1997; Pollard … (more)
Reported previously in association with mucopolysaccharidosis IIIA (MPS IIIA); however it is unclear if a second SGSH variant was identified (Weber et al., 1997; Pollard et al., 2013); Frameshift variant predicted to result in protein truncation, as the last 160 amino acids are replaced with 158 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22976768, 15146460, 9285796, 24314109, 21204211) (less)
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Pathogenic
(Oct 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-III-A
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004201083.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 17, 2024)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-III-A
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001233391.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Leu343Profs*159) in the SGSH gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Leu343Profs*159) in the SGSH gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 160 amino acid(s) of the SGSH protein. This variant is present in population databases (rs778700037, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 15146460, 21204211, 24314109). This variant is also known as c.1026dupC, c.1027_1028insC, and insC1039. ClinVar contains an entry for this variant (Variation ID: 198694). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects SGSH function (PMID: 15146460). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 26, 2019)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV001444995.4
First in ClinVar: Nov 21, 2020 Last updated: Apr 20, 2024 |
Comment:
The alteration results in a premature stop codon: _x000D_ _x000D_ The c.1027dupC (p.L343Pfs*159) alteration, located in coding exon 8 of the SGSH gene, consists of … (more)
The alteration results in a premature stop codon: _x000D_ _x000D_ The c.1027dupC (p.L343Pfs*159) alteration, located in coding exon 8 of the SGSH gene, consists of a duplication of C at position 1027, causing a translational frameshift with a predicted alternate stop codon after 159 amino acids. Frameshifts are typically deleterious in nature; however, this frameshift occurs at the 3' terminus of SGSH, is not expected to trigger nonsense-mediated mRNA decay, and a truncated mutant protein could still be expressed (Maquat, 2004). This alteration impacts the last 160 amino acids of the protein and the exact functional impact of these altered amino acids is unknown at this time; however, this alteration and additional truncating alterations downstream of this alteration have been reported in the literature as disease-causing. The alteration is rare in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.1027dupC alteration was observed in 0.0036% (10/276396) of total alleles studied, with a frequency of 0.0070% (9/127824) in the European (non-Finnish) subpopulation. This alteration has been observed in affected individuals: _x000D_ _x000D_ This alteration has been reported in cohorts of patients with MPS type III, although the specific genotype and phenotype of affected patients were not available (Pollard, 2013; Weber, 1997). This alteration has also been reported as C1039 in the literature. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Nov 03, 2016)
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no assertion criteria provided
Method: clinical testing
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Mucopolysaccharidosis, MPS-III-A
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000486596.2
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Mucopolysaccharidosis type IIIA
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001463875.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Natural history of Sanfilippo syndrome in Spain. | Delgadillo V | Orphanet journal of rare diseases | 2013 | PMID: 24314109 |
Molecular characterization of 355 mucopolysaccharidosis patients reveals 104 novel mutations. | Pollard LM | Journal of inherited metabolic disease | 2013 | PMID: 22976768 |
Incidence and natural history of mucopolysaccharidosis type III in France and comparison with United Kingdom and Greece. | Héron B | American journal of medical genetics. Part A | 2011 | PMID: 21204211 |
Transport, enzymatic activity, and stability of mutant sulfamidase (SGSH) identified in patients with mucopolysaccharidosis type III A. | Muschol N | Human mutation | 2004 | PMID: 15146460 |
Mutation and haplotype analyses in 26 Spanish Sanfilippo syndrome type A patients: possible single origin for 1091delC mutation. | Chabás A | American journal of medical genetics | 2001 | PMID: 11343308 |
Mutational analysis of Sanfilippo syndrome type A (MPS IIIA): identification of 13 novel mutations. | Beesley CE | Journal of medical genetics | 2000 | PMID: 11182930 |
Heparan N-sulfatase gene: two novel mutations and transient expression of 15 defects. | Esposito S | Biochimica et biophysica acta | 2000 | PMID: 10727844 |
Novel mutations in Sanfilippo A syndrome: implications for enzyme function. | Weber B | Human molecular genetics | 1997 | PMID: 9285796 |
Text-mined citations for rs778700037 ...
HelpRecord last updated Apr 20, 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.