Submissions for variant NM_152419.3(HGSNAT):c.1330C>T (p.Arg444Cys)

dbSNP: rs763301637

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV001074429	SCV001240013	uncertain significance	Retinal dystrophy	2019-08-16	criteria provided, single submitter	clinical testing
Undiagnosed Diseases Network, NIH	RCV001251049	SCV001426451	pathogenic	Mucopolysaccharidosis, MPS-III-C	2020-02-07	criteria provided, single submitter	clinical testing
GeneDx	RCV001552003	SCV001772615	uncertain significance	not provided	2020-05-08	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp	RCV002554715	SCV003293969	uncertain significance	Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 444 of the HGSNAT protein (p.Arg444Cys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with retinitis pigmentosa (Invitae). ClinVar contains an entry for this variant (Variation ID: 866424). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155356	SCV003844331	uncertain significance	not specified	2023-02-28	criteria provided, single submitter	clinical testing	Variant summary: HGSNAT c.1330C>T (p.Arg444Cys) 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 allele was found at a frequency of 1.2e-05 in 247910 control chromosomes (gnomAD). c.1330C>T has been reported in the literature in two compound heterozygous siblings affected with Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome C) (Xiao_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant as pathogenic (n=1) or VUS (n=4). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Natera, Inc.	RCV001251049	SCV002083313	uncertain significance	Mucopolysaccharidosis, MPS-III-C	2020-02-10	no assertion criteria provided	clinical testing