Submissions for variant NM_152419.3(HGSNAT):c.1237C>T (p.Pro413Ser)

gnomAD frequency: 0.00038  dbSNP: rs201346206

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000346177	SCV000474013	uncertain significance	Sanfilippo syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196774	SCV001367407	uncertain significance	Retinitis pigmentosa 73	2018-10-15	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3.
Invitae	RCV001240733	SCV001413703	uncertain significance	Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73	2022-09-06	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 413 of the HGSNAT protein (p.Pro413Ser). This variant is present in population databases (rs201346206, gnomAD 0.06%). 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: 363147). 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. 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.
Institute of Human Genetics, University of Goettingen	RCV001256203	SCV001429654	likely pathogenic	Mucopolysaccharidosis, MPS-III-C	2020-08-14	criteria provided, single submitter	clinical testing	The HGSNAT variant c.1237C>T (p.(Pro413Ser)) is found at a population frequency of 0.03% in the gnomAD database, it affects a highly conserved nucleotide and a highly conserved amino acid and there is a moderate physicochemical difference between Pro and Ser. The variant has a pathogenic computational verdict based on 8 pathogenic predictions from BayesDel_addAF, DANN, EIGEN, FATHMM-MKL, M-CAP, MutationTaster, PolyPhen-2 and SIFT vs 2 benign predictions from MVP and REVEL. This variant was found in trans with the known pathogenic HGSNAT mutation c.1622C>T (p.(Ser541Leu); ClinVar Variation ID: 569073) and the phenotype of our patient matched the phenotype typical for Mucopolysaccharidosis type IIIC (Sanfilippo C) patients. Thus, we consider this variant to be likely pathogenic. ACMG criteria used for classification: PM2, PM3, PP2, PP3.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001584092	SCV001821444	uncertain significance	not specified	2021-08-30	criteria provided, single submitter	clinical testing	Variant summary: HGSNAT c.1237C>T (p.Pro413Ser) results in a non-conservative amino acid change located in the Heparan-alpha-glucosaminide N-acetyltransferase, catalytic domain (IPR012429) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 252566 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in HGSNAT causing Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome C) (0.00031 vs 0.001), allowing no conclusion about variant significance. c.1237C>T has been reported in the literature in one individual affected with Parkinsons disease as well as in two control subjects (Robak_2017). The report does not provide unequivocal conclusions about association of the variant with Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome C). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002523685	SCV003678668	uncertain significance	Inborn genetic diseases	2022-11-15	criteria provided, single submitter	clinical testing	The c.1237C>T (p.P413S) alteration is located in exon 12 (coding exon 12) of the HGSNAT gene. This alteration results from a C to T substitution at nucleotide position 1237, causing the proline (P) at amino acid position 413 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Clinical Genetics, Academic Medical Center	RCV001700100	SCV001917235	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001700100	SCV001971027	uncertain significance	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001256203	SCV002083311	uncertain significance	Mucopolysaccharidosis, MPS-III-C	2019-10-28	no assertion criteria provided	clinical testing