VCV000002669.36 - ClinVar

NM_182760.4(SUMF1):c.836C>T (p.Ala279Val)

Germline

Classification

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.

(16)

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/Likely pathogenic

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.836C>T (p.Ala279Val)

Variation ID: 2669 Accession: VCV000002669.36

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p26.1 3: 4417132 (GRCh38) [ NCBI UCSC ] 3: 4458816 (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	Jun 29, 2015	Feb 14, 2024	Dec 30, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_182760.4:c.836C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_877437.2:p.Ala279Val	missense
NM_001164674.2:c.761C>T	NP_001158146.1:p.Ala254Val	missense
NM_001164675.2:c.836C>T	NP_001158147.1:p.Ala279Val	missense
NC_000003.12:g.4417132G>A
NC_000003.11:g.4458816G>A
NG_016225.2:g.55151C>T
	Q8NBK3:p.Ala279Val

... more HGVS ... less HGVS

Protein change

A279V, A254V

Other names

Canonical SPDI

NC_000003.12:4417131:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00020 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00007

1000 Genomes Project 30x 0.00016

Trans-Omics for Precision Medicine (TOPMed) 0.00017

1000 Genomes Project 0.00020

The Genome Aggregation Database (gnomAD) 0.00024

Links

ClinGen: CA115674 UniProtKB: Q8NBK3#VAR_016055 OMIM: 607939.0007 dbSNP: rs137852849 VarSome

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
Gene	OMIM	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.
Multiple sulfatase deficiency	Pathogenic/Likely pathogenic (13)	criteria provided, multiple submitters, no conflicts	Dec 30, 2023	RCV000002788.41
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 24, 2022	RCV000082716.21

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.
Pathogenic (Oct 18, 2013)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000114760.8 First in ClinVar: Jan 17, 2014 Last updated: Jun 29, 2015	Publications: PubMed (3) PubMed: 12757705‚ 12757706‚ 18157819 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SUMF1 Number of individuals with the variant: 3 Sex: mixed
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447395.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Premature birth (present) , Corpus callosum, agenesis of (present) , Subdural hemorrhage (present) , Ventricular septal defect (present) , Abnormal prolactin level (present) , Microcephaly … (more) Premature birth (present) , Corpus callosum, agenesis of (present) , Subdural hemorrhage (present) , Ventricular septal defect (present) , Abnormal prolactin level (present) , Microcephaly (present) , Decreased response to growth hormone stimulation test (present) , Cerebellar ataxia (present) , Global developmental delay (present) (less) Sex: male
Likely pathogenic (Jun 27, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Multiple sulfatase deficiency Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001366616.2 First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP2,PP3.
Pathogenic (Aug 06, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Multiple sulfatase deficiency Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001362112.2 First in ClinVar: Jun 22, 2020 Last updated: Sep 08, 2021	Publications: PubMed (7) PubMed: 12757706‚ 25885655‚ 12757705‚ 26825355‚ 29397290‚ 25373814‚ 18157819 Comment: Variant summary: SUMF1 c.836C>T (p.Ala279Val) results in a non-conservative amino acid change located in the Sulfatase-modifying factor enzyme domain of the encoded protein sequence. Five … (more) Variant summary: SUMF1 c.836C>T (p.Ala279Val) results in a non-conservative amino acid change located in the Sulfatase-modifying factor enzyme domain 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 9.2e-05 in 251232 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SUMF1 causing Multiple Sulfatase Deficiency (9.2e-05 vs 0.0011), allowing no conclusion about variant significance. c.836C>T has been reported in the literature in multiple individuals affected with Multiple Sulfatase Deficiency (example, Ahresn_2018, Dierks_2003, Miskin_2016, Prasad _2014, Sabourdy_2015). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in low enzyme activity across multiple sulfatases (example, Ahresn_2018, Miskin_2016, Sabourdy_2015). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a majority consensus leaning towards a pathogenic/likely pathogenic outcome (VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Sep 05, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Multiple sulfatase deficiency Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002027600.1 First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021
Pathogenic (Apr 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Multiple sulfatase deficiency Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002021988.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Likely pathogenic (Mar 18, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: reference population	Multiple sulfatase deficiency Affected status: unknown Allele origin: germline	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center Accession: SCV000267519.1 First in ClinVar: May 24, 2017 Last updated: May 24, 2017	Publications: PubMed (1) PubMed: 12757706 Number of individuals with the variant: 1 Age: 40-69 years Ethnicity/Population group: East Asian Geographic origin: South Korean
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Multiple sulfatase deficiency Affected status: unknown Allele origin: germline	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill Study: CSER_NCGENES_2 Accession: SCV001423863.1 First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020	Publications: PubMed (7) PubMed: 15146462‚ 12757706‚ 18157819‚ 12757705‚ 26825355‚ 25373814‚ 25885655 Comment: The SUMF1 c.836C>T p.Ala279Val variant is frequently observed in patients with multiple sulfatase deficiency (PMIDs:15146462; 12757706; 18157819; 12757705; 26825355; 25373814; 25885655). Functional studies of this … (more) The SUMF1 c.836C>T p.Ala279Val variant is frequently observed in patients with multiple sulfatase deficiency (PMIDs:15146462; 12757706; 18157819; 12757705; 26825355; 25373814; 25885655). Functional studies of this variant show decreased stability and enzyme activity of the encoded protein (PMID:15146462; 18157819). (less) Number of individuals with the variant: 1
Likely pathogenic (Oct 18, 2016)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: clinical testing	Multiple sulfatase deficiency Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000487122.2 First in ClinVar: Oct 11, 2015 Last updated: Dec 24, 2022	Publications: PubMed (8) PubMed: 15146462‚ 26825355‚ 12757706‚ 25373814‚ 12757705‚ 18157819‚ 25885655‚ 15907468
Pathogenic (Dec 28, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Multiple sulfatase deficiency Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV003799081.2 First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023	Comment: PS3, PS4_Supporting, PM2, PM3, PP3
Pathogenic (May 24, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000490840.4 First in ClinVar: Jun 29, 2015 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate that the variant results in severely decreased formylglycine-generating enzyme protein stability and severely impaired sulfatase-enhancing activity (Schlotawa et al., 2008; Cosma … (more) Published functional studies demonstrate that the variant results in severely decreased formylglycine-generating enzyme protein stability and severely impaired sulfatase-enhancing activity (Schlotawa et al., 2008; Cosma et al., 2004); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29397290, 12757706, 25885655, 18157819, 21224894, 15146462, 19124046, 15907468, 29048999, 33643672, 12757705, 25373814, 26825355) (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Multiple sulfatase deficiency Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV000807622.3 First in ClinVar: May 30, 2018 Last updated: Mar 18, 2023	Publications: PubMed (1) PubMed: 25326635
Pathogenic (Dec 30, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Multiple sulfatase deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001235598.3 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024	Publications: PubMed (7) PubMed: 12757705‚ 12757706‚ 15146462‚ 18157819‚ 25373814‚ 25885655‚ 21224894 Comment: This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 279 of the SUMF1 protein (p.Ala279Val). … (more) This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 279 of the SUMF1 protein (p.Ala279Val). This variant is present in population databases (rs137852849, gnomAD 0.02%). This missense change has been observed in individuals with multiple sulfatase deficiency (PMID: 12757705, 12757706, 15146462, 18157819, 25373814, 25885655). ClinVar contains an entry for this variant (Variation ID: 2669). 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 not expected to disrupt SUMF1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SUMF1 function (PMID: 18157819, 21224894). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (May 16, 2003)	no assertion criteria provided Method: literature only	MULTIPLE SULFATASE DEFICIENCY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000022946.3 First in ClinVar: Apr 04, 2013 Last updated: Sep 17, 2015	Publications: PubMed (2) PubMed: 12757705‚ 12757706 Comment on evidence: In a patient with multiple sulfatase deficiency (MSD; 272200), Dierks et al. (2003) identified compound heterozygosity for a C-to-T transition at nucleotide 836 of the … (more) In a patient with multiple sulfatase deficiency (MSD; 272200), Dierks et al. (2003) identified compound heterozygosity for a C-to-T transition at nucleotide 836 of the SUMF1 gene, resulting in the substitution of a conserved amino acid, ala279 to val (A279V). The second mutation was a frameshift deletion of 1 bp (C) at nucleotide 243 (607939.0008), resulting in a truncated protein. In a patient with moderate MSD, Cosma et al. (2003) identified compound heterozygosity for the A279V mutation and a 1-bp deletion (A) at position -2 of intron 5 (603-2delA; 607939.0016), resulting in skipping of exon 5. (less)
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Multiple sulfatase deficiency Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001460169.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
not provided (-)	no classification provided Method: literature only	Multiple sulfatase deficiency Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000899289.2 First in ClinVar: May 02, 2019 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 30896912 BookShelf: NBK538937 BookShelf: NBK538937
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Comment:

Variant summary: SUMF1 c.836C>T (p.Ala279Val) results in a non-conservative amino acid change located in the Sulfatase-modifying factor enzyme domain 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 9.2e-05 in 251232 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SUMF1 causing Multiple Sulfatase Deficiency (9.2e-05 vs 0.0011), allowing no conclusion about variant significance. c.836C>T has been reported in the literature in multiple individuals affected with Multiple Sulfatase Deficiency (example, Ahresn_2018, Dierks_2003, Miskin_2016, Prasad _2014, Sabourdy_2015). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in low enzyme activity across multiple sulfatases (example, Ahresn_2018, Miskin_2016, Sabourdy_2015). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a majority consensus leaning towards a pathogenic/likely pathogenic outcome (VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

The SUMF1 c.836C>T p.Ala279Val variant is frequently observed in patients with multiple sulfatase deficiency (PMIDs:15146462; 12757706; 18157819; 12757705; 26825355; 25373814; 25885655). Functional studies of this variant show decreased stability and enzyme activity of the encoded protein (PMID:15146462; 18157819).

Comment:

Published functional studies demonstrate that the variant results in severely decreased formylglycine-generating enzyme protein stability and severely impaired sulfatase-enhancing activity (Schlotawa et al., 2008; Cosma et al., 2004); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29397290, 12757706, 25885655, 18157819, 21224894, 15146462, 19124046, 15907468, 29048999, 33643672, 12757705, 25373814, 26825355)

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 279 of the SUMF1 protein (p.Ala279Val). This variant is present in population databases (rs137852849, gnomAD 0.02%). This missense change has been observed in individuals with multiple sulfatase deficiency (PMID: 12757705, 12757706, 15146462, 18157819, 25373814, 25885655). ClinVar contains an entry for this variant (Variation ID: 2669). 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 not expected to disrupt SUMF1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SUMF1 function (PMID: 18157819, 21224894). 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Multiple Sulfatase Deficiency.	Adam MP	-	2019	PMID: 30896912
Complex care of individuals with multiple sulfatase deficiency: Clinical cases and consensus statement.	Ahrens-Nicklas R	Molecular genetics and metabolism	2018	PMID: 29397290
A Patient With Atypical Multiple Sulfatase Deficiency.	Miskin C	Pediatric neurology	2016	PMID: 26825355
Natural disease history and characterisation of SUMF1 molecular defects in ten unrelated patients with multiple sulfatase deficiency.	Sabourdy F	Orphanet journal of rare diseases	2015	PMID: 25885655
Case of multiple sulfatase deficiency and ocular albinism: a diagnostic odyssey.	Prasad C	The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques	2014	PMID: 25373814
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 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
Molecular basis for multiple sulfatase deficiency and mechanism for formylglycine generation of the human formylglycine-generating enzyme.	Dierks T	Cell	2005	PMID: 15907468
Molecular and functional analysis of SUMF1 mutations in multiple sulfatase deficiency.	Cosma MP	Human mutation	2004	PMID: 15146462
The multiple sulfatase deficiency gene encodes an essential and limiting factor for the activity of sulfatases.	Cosma MP	Cell	2003	PMID: 12757706
Multiple sulfatase deficiency is caused by mutations in the gene encoding the human C(alpha)-formylglycine generating enzyme.	Dierks T	Cell	2003	PMID: 12757705
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SUMF1	-	-	-	-
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Text-mined citations for rs137852849 ...

These 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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_182760.4(SUMF1):c.836C>T (p.Ala279Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs137852849 ...