ClinVar Miner

Submissions for variant NM_152419.3(HGSNAT):c.1209G>T (p.Trp403Cys)

gnomAD frequency: 0.00002  dbSNP: rs764206492
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000190846 SCV000800513 uncertain significance Mucopolysaccharidosis, MPS-III-C 2017-04-04 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002500583 SCV002778424 uncertain significance Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73 2022-03-08 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002500583 SCV003440194 uncertain significance Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73 2024-06-04 criteria provided, single submitter clinical testing This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 403 of the HGSNAT protein (p.Trp403Cys). This variant is present in population databases (rs764206492, gnomAD 0.004%). This missense change has been observed in individual(s) with Mucopolysaccharidosis IIIC (PMID: 17033958, 31228227). This variant is also known as W431C. ClinVar contains an entry for this variant (Variation ID: 208817). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HGSNAT protein function. Experimental studies have shown that this missense change affects HGSNAT function (PMID: 19823584, 20583299). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences RCV003417693 SCV004108235 uncertain significance HGSNAT-related disorder 2023-06-06 criteria provided, single submitter clinical testing The HGSNAT c.1209G>T variant is predicted to result in the amino acid substitution p.Trp403Cys. To our knowledge, this variant has always been reported in cis with HGSNAT c.1843G>A (p.Trp403Cys). This haplotype was reported in the homozygous state in patients with Mucopolysaccharidosis IIIC (MPSIIIC) (Hrebicek et al. 2006. PubMed ID: 17033958, reported as p.[W431C;A643T]; Feldhammer et al. 2009. PubMed ID: 19823584). Functional studies indicated that the p.Trp403Cys variant had a >50% reduction in activity when expressed alone and resulted in complete loss of activity when expressed as a haplotype in combination with p.Ala615Thr (Fedele et al. 2010. PubMed ID: 20583299). This variant is reported in 0.0041% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-43046697-G-T). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
OMIM RCV000190846 SCV000245716 pathogenic Mucopolysaccharidosis, MPS-III-C 2006-11-01 no assertion criteria provided literature only

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