Submissions for variant NM_000199.5(SGSH):c.877C>T (p.Pro293Ser)

gnomAD frequency: 0.00004  dbSNP: rs143947056

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255725	SCV000321947	pathogenic	not provided	2023-02-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect due to a significant reduction of enzyme activity (Lee-Chen et al., 2002); Not observed at significant frequency in large population cohorts (gnomAD); 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: 12000360, 25807448, 24816101, 31589614, 30070758, 29930972, 26787381, 22976768, 34991944)
SIB Swiss Institute of Bioinformatics	RCV000409289	SCV000803563	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Likely Pathogenic, for Mucopolysaccharidosis type IIIA (Sanfilippo A), in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (PMID:12000360).
Fulgent Genetics, Fulgent Genetics	RCV000409289	SCV000893481	pathogenic	Mucopolysaccharidosis, MPS-III-A	2024-01-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000409289	SCV000963680	pathogenic	Mucopolysaccharidosis, MPS-III-A	2024-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 293 of the SGSH protein (p.Pro293Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 12000360, 22976768, 26787381; internal data). ClinVar contains an entry for this variant (Variation ID: 265258). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SGSH protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SGSH function (PMID: 12000360). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001266815	SCV001444994	pathogenic	Inborn genetic diseases	2019-12-26	criteria provided, single submitter	clinical testing	The alteration results in an amino acid change:_x000D_ _x000D_ The c.877C>T (p.P293S) alteration is located in coding exon 7 of the SGSH gene. This alteration results from a C to T substitution at nucleotide position 877, causing the proline (P) at amino acid position 293 to be replaced by a serine (S). The alteration is rare in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.877C>T alteration was observed in 0.0035% (10/281908) of total alleles studied, with a frequency of 0.014% (1/7200) in the Other subpopulation. The amino acid change has been observed in affected individuals: _x000D_ _x000D_ This alteration has been described, along with a second disease-causing alteration, in multiple patients with a biochemical diagnosis of MPSIIIA (Lee-Chen, 2002; Lin, 2018; Shapiro, 2016).. The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.P293 amino acid is conserved in available vertebrate species. Functional analysis reveals a damaging effect of the amino acid alteration: _x000D_ _x000D_ Functional analysis demonstrated that protein expressing the p.P293S alteration in COS-7 cells had only trace amounts of enzyme activity (0.1% of wildtype) (Lee-Chen, 2002). The alteration is predicted deleterious by in silico modeling:_x000D_ _x000D_ The p.P293S alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Genome-Nilou Lab	RCV000409289	SCV002045494	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000409289	SCV002765967	pathogenic	Mucopolysaccharidosis, MPS-III-A	2022-11-03	criteria provided, single submitter	clinical testing	Variant summary: SGSH c.877C>T (p.Pro293Ser) results in a non-conservative amino acid change located in the Sulfatase, N-terminal (IPR000917) 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 3.6e-05 in 250522 control chromosomes. c.877C>T has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIA/Sanfilippo Syndrome A (Heron_2011, Lee-Chen_2002, Wijburg_2022), and several of these patients were reported as compound heterozygous, carrying a second (likely) pathogenic variant. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <1% of normal activity. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000409289	SCV004201100	pathogenic	Mucopolysaccharidosis, MPS-III-A	2024-03-28	criteria provided, single submitter	clinical testing
Counsyl	RCV000409289	SCV000486447	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2016-11-12	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000409289	SCV001463878	pathogenic	Mucopolysaccharidosis, MPS-III-A	2020-09-16	no assertion criteria provided	clinical testing