ClinVar Genomic variation as it relates to human health
NM_182760.4(SUMF1):c.536G>C (p.Trp179Ser)
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.
Likely pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_182760.4(SUMF1):c.536G>C (p.Trp179Ser)
Variation ID: 1705576 Accession: VCV001705576.2
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p26.1 3: 4420130 (GRCh38) [ NCBI UCSC ] 3: 4461814 (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 Sep 17, 2022 Jan 6, 2024 Nov 8, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_182760.4:c.536G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_877437.2:p.Trp179Ser missense NM_001164674.2:c.461G>C NP_001158146.1:p.Trp154Ser missense NM_001164675.2:c.536G>C NP_001158147.1:p.Trp179Ser missense NC_000003.12:g.4420130C>G NC_000003.11:g.4461814C>G NG_016225.2:g.52153G>C - Protein change
- W154S, W179S
- Other names
- -
- Canonical SPDI
- NC_000003.12:4420129:C:G
-
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.
-
- 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. |
|||
SUMF1 | - | - |
GRCh38 GRCh37 |
641 | 890 |
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 (2) |
criteria provided, conflicting classifications
|
Nov 8, 2023 | RCV002283890.3 |
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple sulfatase deficiency
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002573061.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 1.00). This variant has been reported to have a damaging effect on substrate binding of the FGly-generating enzyme (FGE) encoded by SUMF1 (PMID: 15907468). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Intellectual disability (present) , Neurodevelopmental delay (present) , Paralysis (present) , Paraplegia (present) , Movement disorder (present) , Synophrys (present) , Absent speech (present) , … (more)
Intellectual disability (present) , Neurodevelopmental delay (present) , Paralysis (present) , Paraplegia (present) , Movement disorder (present) , Synophrys (present) , Absent speech (present) , Abnormal facial shape (present) , Developmental regression (present) , Dysphagia (present) , Hirsutism (present) , Low-set ears (present) , Thick eyebrow (present) , Long eyelashes (present) , Failure to thrive (present) , Slender build (present) (less)
|
|
Likely pathogenic
(Nov 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple sulfatase deficiency
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004223559.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
Variant summary: SUMF1 c.536G>C (p.Trp179Ser) results in a non-conservative amino acid change located in the Sulfatase-modifying factor enzyme domain (IPR005532) of the encoded protein sequence. … (more)
Variant summary: SUMF1 c.536G>C (p.Trp179Ser) results in a non-conservative amino acid change located in the Sulfatase-modifying factor enzyme domain (IPR005532) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251222 control chromosomes (gnomAD). c.536G>C has been reported in the literature in individuals affected with Multiple Sulfatase Deficiency (Dierks_2005, Schlotawa_2008, Adang_2020). These data indicate that the variant may be associated with disease. Functional studies report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Schlotawa_2008, Adang_2020). The following publications have been ascertained in the context of this evaluation (PMID: 32749716, 17657823, 19124046, 15907468, 16368756, 21224894, 18157819, 36959582). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
|
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 |
---|---|---|---|---|
Late infantile form of multiple sulfatase deficiency with a novel missense variant in the SUMF1 gene: case report and review. | Sheth J | BMC pediatrics | 2023 | PMID: 36959582 |
Natural history of multiple sulfatase deficiency: Retrospective phenotyping and functional variant analysis to characterize an ultra-rare disease. | Adang LA | Journal of inherited metabolic disease | 2020 | PMID: 32749716 |
SUMF1 mutations affecting stability and activity of formylglycine generating enzyme predict clinical outcome in multiple sulfatase deficiency. | Schlotawa L | European journal of human genetics : EJHG | 2011 | PMID: 21224894 |
Molecular basis of multiple sulfatase deficiency, mucolipidosis II/III and Niemann-Pick C1 disease - Lysosomal storage disorders caused by defects of non-lysosomal proteins. | Dierks T | Biochimica et biophysica acta | 2009 | PMID: 19124046 |
Molecular analysis of SUMF1 mutations: stability and residual activity of mutant formylglycine-generating enzyme determine disease severity in multiple sulfatase deficiency. | Schlotawa L | Human mutation | 2008 | PMID: 18157819 |
Multiple sulfatase deficiency is due to hypomorphic mutations of the SUMF1 gene. | Annunziata I | Human mutation | 2007 | PMID: 17657823 |
A general binding mechanism for all human sulfatases by the formylglycine-generating enzyme. | Roeser D | Proceedings of the National Academy of Sciences of the United States of America | 2006 | PMID: 16368756 |
Molecular basis for multiple sulfatase deficiency and mechanism for formylglycine generation of the human formylglycine-generating enzyme. | Dierks T | Cell | 2005 | PMID: 15907468 |
Text-mined citations for this variant ...
HelpRecord last updated Feb 04, 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.