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

gnomAD frequency: 0.00002  dbSNP: rs398124544

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082652	SCV000114694	pathogenic	not provided	2013-06-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000082652	SCV000516535	pathogenic	not provided	2021-12-21	criteria provided, single submitter	clinical testing	Observed in a patient with features consistent with mucopolysaccharidosis 3C (MPS 3C) who harbored a second variant in published literature (Fernandez-Marmiesse et al., 2014); Reported with a benign variant, phase unknown, by whole exome sequencing in a patient with late onset retinitis pigmentosa in published literature (Schiff et al., 2020); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 16199547, 33578874, 19479962, 32770643, 31228227, 17033958, 24767253)
Illumina Laboratory Services, 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	2023-12-19	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. Variants that disrupt the donor or acceptor splice site 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). This variant is present in population databases (rs398124544, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with autosomal recessive mucopolysaccharidosis type III (PMID: 17033958, 24767253). This variant is also known as c.1334+1G>A. ClinVar contains an entry for this variant (Variation ID: 96500). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Myriad Genetics, Inc.	RCV000668206	SCV002060173	pathogenic	Mucopolysaccharidosis, MPS-III-C	2021-11-01	criteria provided, single submitter	clinical testing	NM_152419.2(HGSNAT):c.1250+1G>A is a canonical splice variant classified as pathogenic in the context of mucopolysaccharidosis type IIIC. c.1250+1G>A has been observed in cases with relevant disease (PMID: 31228227, 24767253). Functional assessments of this variant are not available in the literature. c.1250+1G>A has been observed in population frequency databases (gnomAD: OTH 0.01%). In summary, NM_152419.2(HGSNAT):c.1250+1G>A is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
MGZ Medical Genetics Center	RCV002288581	SCV002579746	pathogenic	Retinitis pigmentosa 73	2022-01-31	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000668206	SCV001460470	pathogenic	Mucopolysaccharidosis, MPS-III-C	2020-09-16	no assertion criteria provided	clinical testing