ClinVar Miner

Submissions for variant NM_152419.3(HGSNAT):c.1411G>A (p.Glu471Lys) (rs753355844)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255417 SCV000322433 pathogenic not provided 2018-09-06 criteria provided, single submitter clinical testing The E471K variant in the HGSNAT gene has been reported in multiple patients with mucopolysaccharidosis IIIC (MPS IIIC) who were either homozygous for E471K or who also harbored a second pathogenic variant in the HGSNAT gene (Hrebicek et al., 2006; Ruijter et al., 2008; Feldhammer et al., 2009a). Expression of the E471K variant resulted in misfolding of the HGSNAT protein, retention in the endoplasmic reticulum, and negligible heparan acetyl CoA: alpha-glucosaminide N-acetyltransferase (HGSNAT) enzyme activity (Fedele et al., 2010; Feldhammer et al., 2009b). The E471K variant is observed in 1/30,782 alleles (0.0032%) from individuals of South Asian background, and 4/246,216 global alleles (0.0016%), in large population cohorts (Lek et al., 2016). The E471K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret E471K as a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587936 SCV000699952 pathogenic Sanfilippo syndrome 2017-06-05 criteria provided, single submitter clinical testing Variant summary: The HGSNAT c.1411G>A (p.Glu471Lys) variant causes the change of "an acidic residue for a basic one just inside the lysosomal luman (Feldhammer_2009)" involving the alteration of a conserved nucleotide and 3/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a damaging outcome for this variant . This variant was found in 1/120760 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic HGSNAT variant (0.001). The variant was reported in the literature in MPS type IIIC patients both in the homozygous state and in the compound heterozygous state with other pathogenic variants. Additionally, the variant expressed in various cell model systems was shown to have significantly decreased enzyme activity, and to result in production of misfolded HGSNAT protein that is abnormally glycosylated and not targeted to the lysosome (Fedele_2010, Feldhammer_2009). One clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763185 SCV000893785 pathogenic Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000763185 SCV001207109 pathogenic Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73 2020-08-07 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 471 of the HGSNAT protein (p.Glu471Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs753355844, ExAC 0.006%). This variant has been observed in individuals affected with mucopolysaccharidosis type III (PMID: 17033958, 18024218, 19479962). This variant is also known as p.E499K in the literature. ClinVar contains an entry for this variant (Variation ID: 265483). This variant has been reported to affect HGSNAT protein function (PMID: 20583299). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000665568 SCV000789714 likely pathogenic Mucopolysaccharidosis, MPS-III-C 2017-02-13 no assertion criteria provided clinical testing
Natera, Inc. RCV000665568 SCV001460471 pathogenic Mucopolysaccharidosis, MPS-III-C 2020-09-16 no assertion criteria provided clinical testing

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