This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 345 of the SUMF1 protein (p.Arg345Cys). This variant is present in population databases (rs137852852, gnomAD 0.01%). This missense change has been observed in individual(s) with multiple sulfatase deficiency (PMID: 12757706, 21224894). ClinVar contains an entry for this variant (Variation ID: 2675). 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) performed at Invitae indicates that this missense variant is expected to disrupt SUMF1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SUMF1 function (PMID: 21224894). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_182760.4(SUMF1):c.1033C>T (p.Arg345Cys)
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.
(5)
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.
Pathogenic
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_182760.4(SUMF1):c.1033C>T (p.Arg345Cys)
Variation ID: 2675 Accession: VCV000002675.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p26.1 3: 4362236 (GRCh38) [ NCBI UCSC ] 3: 4403920 (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 Jul 3, 2016 Feb 14, 2024 Dec 4, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_182760.4:c.1033C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_877437.2:p.Arg345Cys missense NM_001164674.2:c.958C>T NP_001158146.1:p.Arg320Cys missense NM_001164675.2:c.973C>T NP_001158147.1:p.Arg325Cys missense NC_000003.12:g.4362236G>A NC_000003.11:g.4403920G>A NG_016225.2:g.110047C>T Q8NBK3:p.Arg345Cys - Protein change
- R345C, R325C, R320C
- Other names
- -
- Canonical SPDI
- NC_000003.12:4362235:G:A
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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
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
- 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 |
652 | 910 | |
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. |
|---|---|---|---|---|
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Dec 4, 2023 | RCV000002794.15 |
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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|---|---|---|---|---|---|
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Pathogenic
(Nov 11, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple sulfatase deficiency
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002807235.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Dec 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple sulfatase deficiency
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002123479.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 345 of the SUMF1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 345 of the SUMF1 protein (p.Arg345Cys). This variant is present in population databases (rs137852852, gnomAD 0.01%). This missense change has been observed in individual(s) with multiple sulfatase deficiency (PMID: 12757706, 21224894). ClinVar contains an entry for this variant (Variation ID: 2675). 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) performed at Invitae indicates that this missense variant is expected to disrupt SUMF1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SUMF1 function (PMID: 21224894). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Feb 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple sulfatase deficiency
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004175833.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The missense c.1033C>T(p.Arg345Cys) variant in SUMF1 gene has been reported in homozygous state in multiple individual affected with multiple sulfatase deficiency (Schlotawa L, et. al., … (more)
The missense c.1033C>T(p.Arg345Cys) variant in SUMF1 gene has been reported in homozygous state in multiple individual affected with multiple sulfatase deficiency (Schlotawa L, et. al., 2011; Cosma MP, et. al., 2003). Experimental studies have shown disruption of protein (Schlotawa L, et. al., 2011). The variant is reported with an allele frequency of 0.0004% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Pathogenic. The amino acid change p.Arg345Cys in SUMF1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 345 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 01, 2011)
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no assertion criteria provided
Method: literature only
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MULTIPLE SULFATASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000022952.3
First in ClinVar: Apr 04, 2013 Last updated: Jul 03, 2016 |
Comment on evidence:
In 2 patients with multiple sulfatase deficiency (MSD; 272200), Cosma et al. (2003) identified a C-to-T transition at nucleotide 1033 of the SUMF1 gene, resulting … (more)
In 2 patients with multiple sulfatase deficiency (MSD; 272200), Cosma et al. (2003) identified a C-to-T transition at nucleotide 1033 of the SUMF1 gene, resulting in an arg345-to-cys substitution (R345C). One patient was homozygous for the R345C mutation, while the other was compound heterozygous for R345C and a G-to-A transition at nucleotide 653, resulting in a cys218-to-tyr substitution (C218Y; 607939.0015). Schlotawa et al. (2011) reported a patient with severe late-infantile onset of MSD who was homozygous for the R345C mutation. In vitro functional expression studies in fibrosarcoma cells showed that the mutant protein had normal expression and localized correctly to the ER, but was unstable and was secreted into the medium, The mutant protein retained about 2.0% residual catalytic activity compared to wildtype. Patient fibroblasts showed severely reduced levels of SUMF1. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Multiple sulfatase deficiency
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000899284.2
First in ClinVar: May 02, 2019 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
The missense c.1033C>T(p.Arg345Cys) variant in SUMF1 gene has been reported in homozygous state in multiple individual affected with multiple sulfatase deficiency (Schlotawa L, et. al., 2011; Cosma MP, et. al., 2003). Experimental studies have shown disruption of protein (Schlotawa L, et. al., 2011). The variant is reported with an allele frequency of 0.0004% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Pathogenic. The amino acid change p.Arg345Cys in SUMF1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 345 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
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:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 345 of the SUMF1 protein (p.Arg345Cys). This variant is present in population databases (rs137852852, gnomAD 0.01%). This missense change has been observed in individual(s) with multiple sulfatase deficiency (PMID: 12757706, 21224894). ClinVar contains an entry for this variant (Variation ID: 2675). 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) performed at Invitae indicates that this missense variant is expected to disrupt SUMF1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SUMF1 function (PMID: 21224894). For these reasons, this variant has been classified as Pathogenic.
Comment:
The missense c.1033C>T(p.Arg345Cys) variant in SUMF1 gene has been reported in homozygous state in multiple individual affected with multiple sulfatase deficiency (Schlotawa L, et. al., 2011; Cosma MP, et. al., 2003). Experimental studies have shown disruption of protein (Schlotawa L, et. al., 2011). The variant is reported with an allele frequency of 0.0004% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Pathogenic. The amino acid change p.Arg345Cys in SUMF1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 345 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Multiple Sulfatase Deficiency. | Adam MP | - | 2019 | PMID: 30896912 |
| 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 |
| The multiple sulfatase deficiency gene encodes an essential and limiting factor for the activity of sulfatases. | Cosma MP | Cell | 2003 | PMID: 12757706 |
Text-mined citations for rs137852852 ...
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.