NM_182760.4(SUMF1):c.836C>T (p.Ala279Val) AND Multiple sulfatase deficiency

Germline classification:: Pathogenic/Likely pathogenic (13 submissions)
Last evaluated:: Dec 30, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000002788.41

Allele description [Variation Report for NM_182760.4(SUMF1):c.836C>T (p.Ala279Val)]

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

Gene:

SUMF1:sulfatase modifying factor 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p26.1

Genomic location:

Preferred name:

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

HGVS:

NC_000003.12:g.4417132G>A
NG_016225.2:g.55151C>T
NM_001164674.2:c.761C>T
NM_001164675.2:c.836C>T
NM_182760.4:c.836C>TMANE SELECT
NP_001158146.1:p.Ala254Val
NP_001158147.1:p.Ala279Val
NP_001158147.1:p.Ala279Val
NP_877437.2:p.Ala279Val
NP_877437.2:p.Ala279Val
NC_000003.11:g.4458816G>A
NM_001164675.1:c.836C>T
NM_182760.3:c.836C>T
Q8NBK3:p.Ala279Val

Protein change:

A254V; ALA279VAL

Links:

UniProtKB: Q8NBK3#VAR_016055; OMIM: 607939.0007; dbSNP: rs137852849

NCBI 1000 Genomes Browser:

rs137852849

Molecular consequence:

NM_001164674.2:c.761C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001164675.2:c.836C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_182760.4:c.836C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Multiple sulfatase deficiency (MSD)
Synonyms:: Juvenile sulfatidosis; Mucosulfatidosis; Multiple Sulfatase Deficiency Disease; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010088; MedGen: C0268263; Orphanet: 585; OMIM: 272200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000022946	OMIM	no assertion criteria provided	Pathogenic (May 16, 2003)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 12757705, 12757706
SCV000267519	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 18, 2016)	germline	reference population	PubMed (2) [See all records that cite these PMIDs] 12757706, 25741868
SCV000487122	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Oct 18, 2016)	unknown	clinical testing	PubMed (8) [See all records that cite these PMIDs] 15146462, 26825355, 12757706, 25373814, 12757705, 18157819, 25885655, 15907468 mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV000807622	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 25326635
SCV000899289	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001235598	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 30, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 12757705, 12757706, 15146462, 25373814, 25885655, 18157819, 21224894, 28492532
SCV001362112	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 6, 2021)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 12757706, 25885655, 12757705, 26825355, 29397290, 25373814, 18157819 Citation Link,
SCV001366616	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 27, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001423863	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill - CSER_NCGENES_2	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	research	PubMed (8) [See all records that cite these PMIDs] 15146462, 12757706, 18157819, 12757705, 26825355, 25373814, 25885655, 25741868
SCV001460169	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002021988	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 29, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002027600	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 5, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003799081	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 28, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing, literature only, research
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
East Asian	germline	unknown	1	not provided	not provided	not provided	not provided	reference population

Citations

PubMed

Molecular basis for multiple sulfatase deficiency and mechanism for formylglycine generation of the human formylglycine-generating enzyme.

Dierks T, Dickmanns A, Preusser-Kunze A, Schmidt B, Mariappan M, von Figura K, Ficner R, Rudolph MG.

Cell. 2005 May 20;121(4):541-552. doi: 10.1016/j.cell.2005.03.001.

PubMed [citation]

PMID:: 15907468

Molecular findings among patients referred for clinical whole-exome sequencing.

Yang Y, Muzny DM, Xia F, Niu Z, Person R, Ding Y, Ward P, Braxton A, Wang M, Buhay C, Veeraraghavan N, Hawes A, Chiang T, Leduc M, Beuten J, Zhang J, He W, Scull J, Willis A, Landsverk M, Craigen WJ, Bekheirnia MR, et al.

JAMA. 2014 Nov 12;312(18):1870-9. doi: 10.1001/jama.2014.14601.

PubMed [citation]

PMID:: 25326635
PMCID:: PMC4326249

See all PubMed Citations (14)

Details of each submission

From OMIM, SCV000022946.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center, SCV000267519.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	East Asian	1	not provided	not provided	reference population	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

From Counsyl, SCV000487122.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV000807622.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV000899289.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001235598.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001362112.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001366616.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP2,PP3.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill - CSER_NCGENES_2, SCV001423863.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (8)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

From Natera, Inc., SCV001460169.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002021988.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002027600.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV003799081.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

PS3, PS4_Supporting, PM2, PM3, PP3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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