ClinVar Miner

Submissions for variant NM_152419.3(HGSNAT):c.372-2A>G (rs483352896)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586364 SCV000699954 pathogenic Sanfilippo syndrome 2016-08-18 criteria provided, single submitter clinical testing Variant summary: The HGSNAT c.372-2A>G variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict loss of a canonical splicing acceptor site. ESEfinder predicts gain of binding motif for RNA splicing enhancer SRp40. This variant was found in 2/89484 control chromosomes at a frequency of 0.0000224, which does not exceed the estimated maximal expected allele frequency of a pathogenic HGSNAT variant (0.001). This variant has been reported in multiple MPSIIIC patients both as homozygotes and compound heterozygotes. Functional studies showed that this variant cause aberrant splicing and significantly decreased enzyme activity. In addition, multiple reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV001067306 SCV001232360 pathogenic Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73 2020-10-07 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 3 of the HGSNAT gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs483352896, ExAC 0.03%). This variant has been observed in individuals affected with mucopolysaccharidosis type III/Sanfilippo syndrome (PMID: 20825431, 18518886). ClinVar contains an entry for this variant (Variation ID: 1236). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 20825431, 18518886). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HGSNAT are known to be pathogenic (PMID: 17033958, 19479962). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000001295 SCV000021445 pathogenic Mucopolysaccharidosis, MPS-III-C 2011-10-01 no assertion criteria provided literature only
Counsyl RCV000001295 SCV000792528 pathogenic Mucopolysaccharidosis, MPS-III-C 2017-06-29 no assertion criteria provided clinical testing
Natera, Inc. RCV000001295 SCV001460466 pathogenic Mucopolysaccharidosis, MPS-III-C 2020-09-16 no assertion criteria provided clinical testing

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