Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000002796 | SCV004122659 | likely pathogenic | Multiple sulfatase deficiency | 2023-10-09 | criteria provided, single submitter | clinical testing | Variant summary: SUMF1 c.653G>A (p.Cys218Tyr) results in a non-conservative amino acid change located in the Sulfatase-modifying factor enzyme (IPR005532) of the encoded protein sequence, and Cys218 has been suggested to be involved in SUMF1 protein stability (Dierks_2005). 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 8e-06 in 251368 control chromosomes. c.653G>A has been reported at a compound heterozygous state along with a pathogenic missense variant in at-least one individual affected with Multiple Sulfatase Deficiency (example, Cosma_2003). At least one publication reports experimental evidence evaluating an impact on protein function (Cosma_2003). The most pronounced variant effect results in <10% of normal activity in fibroblasts from the patient of multiple sulfatase deficiency, carrying p.Cys218Tyr and p.Arg345Cys at a compound heterozygous state, in whom p.Arg345Cys has shown to significantly compromised sulfatase activities (PMID: 21224894). These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 12757706, 15907468). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Invitae | RCV000002796 | SCV004292198 | likely pathogenic | Multiple sulfatase deficiency | 2023-09-08 | criteria provided, single submitter | clinical testing | Experimental studies have shown that this missense change affects SUMF1 function (PMID: 15146462). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 2677). This missense change has been observed in individual(s) with multiple sulfatase deficiency (MSD) (PMID: 15146462). This variant is present in population databases (rs137852854, gnomAD 0.003%). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 218 of the SUMF1 protein (p.Cys218Tyr). |
| OMIM | RCV000002796 | SCV000022954 | pathogenic | Multiple sulfatase deficiency | 2003-05-16 | no assertion criteria provided | literature only |