ClinVar Miner

Submissions for variant NM_152419.3(HGSNAT):c.493+1G>A (rs193066451)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000001289 SCV000791535 pathogenic Mucopolysaccharidosis, MPS-III-C 2017-05-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763183 SCV000893783 pathogenic Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780343 SCV000917526 pathogenic Sanfilippo syndrome 2018-08-13 criteria provided, single submitter clinical testing Variant summary: HGSNAT c.493+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: Four predict the variant abolishes a 5 splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing. The variant allele was found at a frequency of 4.7e-05 in 276088 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in HGSNAT causing Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome C) (4.7e-05 vs 0.001), allowing no conclusion about variant significance. c.493+1G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome C) (Fan_2006, Hrebicek_2006). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000763183 SCV001233491 pathogenic Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73 2020-08-08 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 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 (rs193066451, ExAC 0.04%). This variant has been observed in several individuals affected with mucopolysaccharidosis type III (PMID: 16960811, 17033958). This variant is also known as c.577+1G>A, p.P193HfsX20 in the literature. ClinVar contains an entry for this variant (Variation ID: 1230). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000001289 SCV000021439 pathogenic Mucopolysaccharidosis, MPS-III-C 2006-10-01 no assertion criteria provided literature only
Natera, Inc. RCV000001289 SCV001460467 pathogenic Mucopolysaccharidosis, MPS-III-C 2020-09-16 no assertion criteria provided clinical testing

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