ClinVar Miner

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

dbSNP: rs763301637
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Total submissions: 6
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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
Invitae 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

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