ClinVar Miner

Submissions for variant NM_152419.3(HGSNAT):c.1267G>T (p.Gly423Trp) (rs1064795522)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478090 SCV000571415 likely pathogenic not provided 2016-08-17 criteria provided, single submitter clinical testing A G423W variant that is likely pathogenic was identified in the HGSNAT gene. It has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G423W variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G423W variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, this variant is located in the hydrophilic lumenal domain of the HGSNAT enzyme. Variants in this region (including the adjacent G424S variant) resulted in protein mis-folding (Feldhammer et al. 2009). In summary, we interpret this variant as likely pathogenic; however, the possibility that it is benign cannot be excluded.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000478090 SCV000699949 uncertain significance not provided 2017-06-05 criteria provided, single submitter clinical testing Variant summary: The HGSNAT c.1267G>T (p.Gly423Trp) variant is located in the lysosomal lumen (Feldhammer_2009; PMID 19479962) involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a damaging outcome for this variant. However, these predictions have yet to be functionally assessed. This variant is absent in 76944 control chromosomes (ExAC). In addition, one clinical diagnostic laboratory classified this variant as likely pathogenic. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Although a poster abstract does indicate that the variant did affect protein function, along with a nearby variant, G424S, has been reported as pathogenic. However, due to absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
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

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