ClinVar Miner

Submissions for variant NM_152419.3(HGSNAT):c.1250+1G>A (rs398124544)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000082652 SCV000114694 pathogenic not provided 2013-06-18 criteria provided, single submitter clinical testing
GeneDx RCV000082652 SCV000516535 pathogenic not provided 2015-04-28 criteria provided, single submitter clinical testing The c.1250+1G>A variant in the HGSNAT gene has been reported previously (reported asc.1334+1G>A due to alternate nomenclature) in an individual with mucopolysaccharidosis IIIC whoharbored a nonsense variant on the other allele (Hrebícek et al., 2006). This splice site variant destroys the canonical splice donor site in intron 12. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.1250+1G>A variant was not observed in approximately 6200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1250+1G>A as a pathogenic variant.
Counsyl RCV000668206 SCV000792771 pathogenic Mucopolysaccharidosis, MPS-III-C 2017-07-12 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000668206 SCV000916230 likely pathogenic Mucopolysaccharidosis, MPS-III-C 2017-04-28 criteria provided, single submitter clinical testing The HGSNAT c.1250+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.1250+1G>A variant has been reported in two studies and is found in a compound heterozygous state in two patients with mucopolysaccharidosis, type III, one of whom had another known pathogenic variant in trans (Hrebícek et al. 2006; Fernández-Marmiesse et al. 2014). The c.1250+1G>A variant was absent from 200 control alleles and is reported at a frequency of 0.00001 in the European (non-Finnish) population from the Exome Aggregation Consortium but this is based on one allele in a region of good sequencing coverage so the variant is presumed to be rare. Based on the evidence and the potential impact of splice donor variants, the c.1250+1G>A variant is classified as likely pathogenic for mucopolysaccharidosis, type III. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV001065437 SCV001230395 pathogenic Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73 2020-10-31 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 12 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 (rs398124544, ExAC 0.001%). This variant has been observed in individual(s) with autosomal recessive mucopolysaccharidosis type III (PMID: 17033958, 24767253). ClinVar contains an entry for this variant (Variation ID: 96500). This variant has also been reported as c.1334+1G>A. 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.
Blueprint Genetics RCV001074721 SCV001240314 likely pathogenic Retinal dystrophy 2019-04-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192639 SCV001360893 pathogenic Sanfilippo syndrome 2019-10-14 criteria provided, single submitter clinical testing Variant summary: HGSNAT c.1250+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. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 249078 control chromosomes (gnomAD). c.1250+1G>A has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome C)(Feldhammer_2009, Fernandez-Marmiesse_2014, Hrebicek_2006, Martins_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions (evaluation after 2014) cite the variant twice as pathogenic and once as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc. RCV000668206 SCV001460470 pathogenic Mucopolysaccharidosis, MPS-III-C 2020-09-16 no assertion criteria provided clinical testing

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