Submissions for variant NM_152419.3(HGSNAT):c.688A>G (p.Thr230Ala)

gnomAD frequency: 0.00001  dbSNP: rs758464800

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001164231	SCV001326344	uncertain significance	Mucopolysaccharidosis, MPS-III-C	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV001882526	SCV002302753	uncertain significance	Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73	2022-06-26	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 230 of the HGSNAT protein (p.Thr230Ala). This variant is present in population databases (rs758464800, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with HGSNAT-related conditions. ClinVar contains an entry for this variant (Variation ID: 911657). 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 not expected to disrupt HGSNAT protein function. 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001796376	SCV002037038	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001796376	SCV002038455	likely benign	not provided		no assertion criteria provided	clinical testing