ClinVar Miner

Submissions for variant NM_000199.5(SGSH):c.1139A>G (p.Gln380Arg) (rs144143780)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000309724 SCV000329515 pathogenic not provided 2021-10-30 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 (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25807448, 9285796, 26787381, 24875751, 24816101, 21061399, 29023963, 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.
Invitae RCV000666337 SCV000954324 pathogenic Mucopolysaccharidosis, MPS-III-A 2020-10-23 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 380 of the SGSH protein (p.Gln380Arg). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs144143780, ExAC 0.02%). This variant has been observed in combination with other pathogenic variants in SGSH in several individuals affected with mucopolysaccharidosis Type IIIA (PMID: 9285796, 21061399, 29023963). ClinVar contains an entry for this variant (Variation ID: 279891). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Nilou-Genome Lab RCV000666337 SCV002045486 pathogenic Mucopolysaccharidosis, MPS-III-A 2021-11-07 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 pathogenic Mucopolysaccharidosis 2019-09-04 no assertion criteria 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

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