ClinVar Miner

Submissions for variant NM_152419.3(HGSNAT):c.234+1G>A (rs483352908)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000153361 SCV000202845 pathogenic not provided 2014-03-31 criteria provided, single submitter clinical testing
Invitae RCV000652843 SCV000774715 pathogenic Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73 2020-09-27 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 2 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 (rs483352908, ExAC 0.02%). This variant has been reported as the most common cause of mucopolysaccharidosis type IIIC in Spain and Morocco, although it has also been reported in other populations (PMID: 17033958, 18024218, 19823584, 20825431, 23301227). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 30832). Experimental studies have shown that this splice site change leads to the out-of-frame skipping of exon 2 (PMID: 20825431). 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, 25859010). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000023817 SCV000795857 pathogenic Mucopolysaccharidosis, MPS-III-C 2017-11-21 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001074236 SCV001239809 pathogenic Retinal dystrophy 2019-04-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192638 SCV001360892 pathogenic Sanfilippo syndrome 2019-01-17 criteria provided, single submitter clinical testing Variant summary: HGSNAT c.234+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that supports these predictions (Matos_2014). The variant allele was found at a frequency of 4.7e-05 in 232180 control chromosomes (gnomAD). c.234+1G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome C)(Ruijter_2008, Matos_2014), which homozygous patients were found to have a significant decrease in enzyme activity (Ruijter_2008). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000023817 SCV000045108 pathogenic Mucopolysaccharidosis, MPS-III-C 2011-10-01 no assertion criteria provided literature only

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