Submissions for variant NM_182760.4(SUMF1):c.463T>C (p.Ser155Pro)

gnomAD frequency: 0.00009  dbSNP: rs137852850

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082715	SCV000114759	pathogenic	not provided	2013-09-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000002791	SCV000487156	likely pathogenic	Multiple sulfatase deficiency	2016-10-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000002791	SCV000700008	pathogenic	Multiple sulfatase deficiency	2017-03-02	criteria provided, single submitter	clinical testing	Variant summary: The SUMF1 c.463T>C (p.Ser155Pro) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 5/121384 control chromosomes at a frequency of 0.0000412, which does not exceed the estimated maximal expected allele frequency of a pathogenic SUMF1 variant (0.001118). The variant was reported in numerous affected individuals in the literature in both the homozygous and compound heterozygous state, and functional evidence has showed patients have a drastic reduction in sulfatase activity compared to wild-type. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic.
Invitae	RCV000002791	SCV000820502	pathogenic	Multiple sulfatase deficiency	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 155 of the SUMF1 protein (p.Ser155Pro). This variant is present in population databases (rs137852850, gnomAD 0.2%). This missense change has been observed in individual(s) with multiple sulfatase deficiency (PMID: 12757706, 16125993, 21224894, 25885655, 27344646). ClinVar contains an entry for this variant (Variation ID: 2672). 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: 15146462, 17657823, 21224894). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000082715	SCV001715802	pathogenic	not provided	2019-09-30	criteria provided, single submitter	clinical testing	PS3, PS4_moderate, PM2, PP4, PP5
GeneDx	RCV000082715	SCV001827005	pathogenic	not provided	2022-10-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with impaired enzymatic activity compared to wildtype (Cosma et al., 2004; Shlotawa et al., 2011); This variant is associated with the following publications: (PMID: 18305113, 29479672, 29048999, 21224894, 12757706, 15146462, 29972788, 29899769, 27344646, 31980526, 31589614)
Genome-Nilou Lab	RCV000002791	SCV002027613	pathogenic	Multiple sulfatase deficiency	2021-09-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000082715	SCV004704434	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	SUMF1: PM3:Strong, PM2, PM5, PP4, PS3:Supporting
OMIM	RCV000002791	SCV000022949	pathogenic	Multiple sulfatase deficiency	2011-03-01	no assertion criteria provided	literature only
GeneReviews	RCV000002791	SCV000899286	not provided	Multiple sulfatase deficiency		no assertion provided	literature only
Natera, Inc.	RCV000002791	SCV001460172	pathogenic	Multiple sulfatase deficiency	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000082715	SCV001551226	likely pathogenic	not provided		no assertion criteria provided	clinical testing