Submissions for variant NM_000199.5(SGSH):c.1129C>T (p.Arg377Cys)

gnomAD frequency: 0.00004  dbSNP: rs772311757

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001246288	SCV001419631	pathogenic	Mucopolysaccharidosis, MPS-III-A	2023-06-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 377 of the SGSH protein (p.Arg377Cys). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SGSH function (PMID: 10727844, 12000360). 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 SGSH protein function. ClinVar contains an entry for this variant (Variation ID: 559103). This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 9554748, 12000360, 19099774, 21910976). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs772311757, gnomAD 0.02%).
Ambry Genetics	RCV001266348	SCV001444522	pathogenic	Inborn genetic diseases	2018-09-24	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001246288	SCV002045488	pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001246288	SCV002500296	pathogenic	Mucopolysaccharidosis, MPS-III-A	2022-03-10	criteria provided, single submitter	clinical testing	Variant summary: SGSH c.1129C>T (p.Arg377Cys) results in a non-conservative amino acid change in 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 250934 control chromosomes. c.1129C>T has been reported in the literature as homozygous and compound heterozygous genotypes in individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (example, Di Natale_1998, Espositio_2000, Heron_2011, Quesleti_2011, Lee-Chen_2002). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Esposito_2000). The most pronounced variant effect results in <10% of Heparan N-sulfatase activity of this mutant transiently transfected in COS cells. Four 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. Based on the evidence outlined above, the variant was classified as pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV001246288	SCV002822860	likely pathogenic	Mucopolysaccharidosis, MPS-III-A		criteria provided, single submitter	clinical testing	The homozygous missense variation in exon 8 of SGSH gene that results in the amino acid substitution to cysteine for arginine at codon of 377 was detected. The variant c.1129C>T (p.Arg377Cys) has not been reported in 1000 genome and has a MAF of 0.004% in the gnomAD database. The insilico prediction of the variant is dIsease causing by DANN, FATHMM, SIFT, PROVEAN and MutationTaster.
Baylor Genetics	RCV001246288	SCV004201105	pathogenic	Mucopolysaccharidosis, MPS-III-A	2023-08-14	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000676150	SCV000801898	pathogenic	not provided	2017-05-15	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001246288	SCV002095121	pathogenic	Mucopolysaccharidosis, MPS-III-A	2020-09-16	no assertion criteria provided	clinical testing