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

gnomAD frequency: 0.00013  dbSNP: rs193066451

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000763183	SCV001233491	pathogenic	Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73	2023-12-26	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. 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 (rs193066451, gnomAD 0.04%). Disruption of this splice site has been observed in individuals with mucopolysaccharidosis type III (PMID: 16960811, 17033958). This variant is also known as c.577+1G>A, p.P193HfsX20. 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. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000001289	SCV002060389	pathogenic	Mucopolysaccharidosis, MPS-III-C	2021-11-10	criteria provided, single submitter	clinical testing	NM_152419.2(HGSNAT):c.493+1G>A is a canonical splice variant classified as pathogenic in the context of mucopolysaccharidosis type IIIC. c.493+1G>A has been observed in cases with relevant disease (PMID: 16960811, 31228227). Functional assessments of this variant are not available in the literature. c.493+1G>A has been observed in population frequency databases (gnomAD: AFR 0.04%). In summary, NM_152419.2(HGSNAT):c.493+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.
Ambry Genetics	RCV002512639	SCV003555614	pathogenic	Inborn genetic diseases	2022-01-31	criteria provided, single submitter	clinical testing	The c.493+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 4 of the HGSNAT gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from gnomAD, the A allele has an overall frequency of 0.01% (14/279402) of total alleles studied. The highest observed frequency was 0.04% (10/24170) of African alleles. This mutation has been reported in the homozygous and compound heterozygous state in individuals with mucopolysaccharidosis type IIIC (Hrebícek, 2006; Fan, 2006). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Based on the available evidence, this alteration is 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