Submissions for variant NM_000199.5(SGSH):c.1139A>G (p.Gln380Arg)

gnomAD frequency: 0.00003  dbSNP: rs144143780

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000309724	SCV000329515	pathogenic	not provided	2023-01-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25807448, 9285796, 26787381, 24875751, 24816101, 21061399, 29023963, 34991944, 11509012)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000666337	SCV000920206	pathogenic	Mucopolysaccharidosis, MPS-III-A	2018-09-24	criteria provided, single submitter	clinical testing	Variant summary: SGSH c.1139A>G (p.Gln380Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 246122 control chromosomes. c.1139A>G has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating SGSH enzyme activity and showed the variant results in <10% of normal activity (Knottnerus_2017). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000666337	SCV000954324	pathogenic	Mucopolysaccharidosis, MPS-III-A	2024-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 380 of the SGSH protein (p.Gln380Arg). This variant is present in population databases (rs144143780, gnomAD 0.009%). This missense change has been observed in individual(s) with mucopolysaccharidosis Type IIIA (PMID: 9285796, 21061399, 29023963). ClinVar contains an entry for this variant (Variation ID: 279891). 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 not expected to disrupt SGSH protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000666337	SCV002045486	pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-11-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000666337	SCV002812754	pathogenic	Mucopolysaccharidosis, MPS-III-A	2024-02-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000666337	SCV004201102	pathogenic	Mucopolysaccharidosis, MPS-III-A	2024-03-28	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000309724	SCV005198225	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
Counsyl	RCV000666337	SCV000790612	pathogenic	Mucopolysaccharidosis, MPS-III-A	2017-04-04	no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000309724	SCV000801897	likely pathogenic	not provided	2017-05-15	no assertion criteria provided	clinical testing
GeneReviews	RCV001030814	SCV001194303	not provided	Mucopolysaccharidosis		no assertion provided	literature only
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000309724	SCV002036068	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000309724	SCV002038366	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000666337	SCV002095120	pathogenic	Mucopolysaccharidosis, MPS-III-A	2020-10-24	no assertion criteria provided	clinical testing