Submissions for variant NM_152419.3(HGSNAT):c.1267G>T (p.Gly423Trp)

dbSNP: rs1064795522

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478090	SCV000571415	pathogenic	not provided	2023-04-19	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on protein maturation, enzymatic activity, and lysosomal targeting/processing (Martins et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31228227, 35848209)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330719	SCV000699949	likely pathogenic	Sanfilippo syndrome	2023-08-30	criteria provided, single submitter	clinical testing	Variant summary: HGSNAT c.1267G>T (p.Gly423Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 241552 control chromosomes. c.1267G>T has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome C) (Martins_2019, Xiao_2022). At least one publication reports experimental evidence evaluating an impact on protein function demonstrates that this variant shows negligible enzyme activity (Martins_2010) . The following publications have been ascertained in the context of this evaluation (PMID: 31228227, 35848209). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as pathogenic/likely pathogenic (n=3) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Undiagnosed Diseases Network, NIH	RCV000626050	SCV000746670	uncertain significance	Mucopolysaccharidosis, MPS-III-C	2017-08-09	criteria provided, single submitter	clinical testing	Two heterozygous variants of unknown significance, c.1042G>A (p.V348M) and c.1267G>T (p.G423W) were detected in the HGSNAT gene in this individual. Whole exome sequencing and Sanger confirmation showed that the father is heterozygous for the p.V348M change, and the mother is heterozygous for the p.G423W change. Our data indicate that the two changes in HGSNAT are in trans (compound heterozygous) configuration.
Blueprint Genetics	RCV001074815	SCV001240413	likely pathogenic	Retinal dystrophy	2019-07-11	criteria provided, single submitter	clinical testing
Invitae	RCV001865466	SCV002272474	likely pathogenic	Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73	2021-06-02	criteria provided, single submitter	clinical testing	Experimental studies have shown that this variant affects HGSNAT protein function (PMID: 31228227). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 HGSNAT protein function. This variant has been observed in individual(s) with mucopolysaccharidosis type IIIC (PMID: 31228227). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 422050). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with tryptophan at codon 423 of the HGSNAT protein (p.Gly423Trp). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and tryptophan.