Submissions for variant NM_152419.3(HGSNAT):c.1031G>A (p.Arg344His)

gnomAD frequency: 0.00004  dbSNP: rs766835582

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000666423	SCV000790712	likely pathogenic	Mucopolysaccharidosis, MPS-III-C	2017-04-05	criteria provided, single submitter	clinical testing
Invitae	RCV001383040	SCV001582049	pathogenic	Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73	2023-09-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 344 of the HGSNAT protein (p.Arg344His). This variant is present in population databases (rs766835582, gnomAD 0.02%). This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 17033958). This variant is also known as c.1115G>A (p.R372H). ClinVar contains an entry for this variant (Variation ID: 551378). 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 disrupts the p.Arg344 amino acid residue in HGSNAT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17033958, 18024218). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV002254940	SCV002526185	likely pathogenic	not provided	2021-12-08	criteria provided, single submitter	clinical testing	Identified in a patient with mucopolysaccharidosis IIIC in the presence of a second HGSNAT variant of uncertain significance of unknown phase in published literature (Hrebicek M et al., 2006); Published functional studies demonstrate reduced enzyme activity with a misfolded and abnormally glycosylated protein that was not targeted to the lysosome and instead retained in the endoplasmic reticulum (Feldhammer M et al., 2009); This variant is associated with the following publications: (PMID: 27491071, 17033958, 19823584, 19479962)
Lifecell International Pvt. Ltd	RCV000666423	SCV003915920	pathogenic	Mucopolysaccharidosis, MPS-III-C		criteria provided, single submitter	clinical testing	A Homozygote Missense variant c.1031G>A in Exon 11 of the HGSNAT gene that results in the amino acid substitution p.Arg344His was identified. The observed variant has a maximum allele frequency of 0.00004/0.00003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/LikelyPathogenic(Variant ID 551378 ).This variant has been previously reported in Mathew F et al., 2009. Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.