ClinVar Miner

Submissions for variant NM_182760.4(SUMF1):c.836C>T (p.Ala279Val) (rs137852849)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000082716 SCV000114760 pathogenic not provided 2013-10-18 criteria provided, single submitter clinical testing
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000002788 SCV000267519 likely pathogenic Multiple sulfatase deficiency 2016-03-18 criteria provided, single submitter reference population
Counsyl RCV000002788 SCV000487122 likely pathogenic Multiple sulfatase deficiency 2016-10-18 criteria provided, single submitter clinical testing
GeneDx RCV000082716 SCV000490840 pathogenic not provided 2018-07-18 criteria provided, single submitter clinical testing The A279V missense variant in the SUMF1 gene has been reported previously in numerous individuals with multiple sulfatase deficiency (MSD) (Cosma et al., 2003; Dierks et al., 2003; Cosma et al., 2004; Schlotawa et al., 2008; Sabourdy et al., 2015; Prasad et al., 2014; Miskin et al., 2016). Functional studies found that A279V results in severely decreased formylglycine-generating enzyme protein stability and severely impaired sulfatase-enhancing activity (Schlotawa et al., 2008; Cosma et al., 2004). In summary, we interpret A279V as a pathogenic variant.
Baylor Genetics RCV000002788 SCV000807622 uncertain significance Multiple sulfatase deficiency 2017-09-01 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found once in our laboratory in trans with a chromosomal deletion in a 5-year-old male with developmental regression, intellectual disability, hypotonia, seizures, spastic quadriplegia, dysmorphisms, joint contractures, optic nerve atrophy, severe ichthyosis. Heterozygotes for this variant are expected to be asymptomatic carriers.
Invitae RCV000002788 SCV001235598 pathogenic Multiple sulfatase deficiency 2019-11-04 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 279 of the SUMF1 protein (p.Ala279Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs137852849, ExAC 0.01%). This variant has been observed in several individuals affected with multiple sulfatase deficiency (PMID: 12757706, 15146462, 12757705, 18157819, 25885655, 25373814.). ClinVar contains an entry for this variant (Variation ID: 2669). This variant has been reported to affect SUMF1 protein activity and stability (PMID: 18157819, 21224894). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000002788 SCV001362112 pathogenic Multiple sulfatase deficiency 2019-02-08 criteria provided, single submitter clinical testing Variant summary: The variant, 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 0.00011 in 276948 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in SUMF1 causing Multiple Sulfatase Deficiency (0.00011 vs 0.0011), allowing no conclusion about variant significance. The variant, c.836C>T has been reported in the literature in multiple individuals affected with Multiple Sulfatase Deficiency (Ahresn_2018, Dierks_2003, Miskin_2016, Prasad _2014, Sabourdy_2015). These data indicate that the variant is very likely to be associated with disease. In few patients, the variant was associated with milder form of MSD with slow disease progression (Cosma_2003, Schlotawa_2008). Multiple publications showed low enzyme activity across multiple sulfatases (Ahresn_2018, Miskin_2016, Sabourdy_2015). Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant three times as likely pathogenic/pathogenic and once as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000002788 SCV001366616 likely pathogenic Multiple sulfatase deficiency 2019-06-27 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP2,PP3.
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV000002788 SCV001423863 likely pathogenic Multiple sulfatase deficiency criteria provided, single submitter research 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).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000082716 SCV001447395 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
OMIM RCV000002788 SCV000022946 pathogenic Multiple sulfatase deficiency 2003-05-16 no assertion criteria provided literature only
GeneReviews RCV000002788 SCV000899289 pathogenic Multiple sulfatase deficiency 2019-01-03 no assertion criteria provided literature only
Natera, Inc. RCV000002788 SCV001460169 pathogenic Multiple sulfatase deficiency 2020-09-16 no assertion criteria provided clinical testing

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