Submissions for variant NM_152419.3(HGSNAT):c.1516C>T (p.Arg506Ter)

gnomAD frequency: 0.00001  dbSNP: rs747240928

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000667348	SCV000791782	pathogenic	Mucopolysaccharidosis, MPS-III-C	2017-05-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001040598	SCV001204182	pathogenic	Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73	2023-08-07	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 552134). This premature translational stop signal has been observed in individuals with mucopolysaccharidosis type III C (PMID: 17033958). This variant is present in population databases (rs747240928, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg506*) in the HGSNAT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HGSNAT are known to be pathogenic (PMID: 17033958, 19479962).
GeneDx	RCV001556095	SCV001777613	pathogenic	not provided	2020-06-15	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21384162, 19479962, 17033958, 25525159)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222590	SCV002500823	pathogenic	Sanfilippo syndrome	2022-03-31	criteria provided, single submitter	clinical testing	Variant summary: HGSNAT c.1516C>T (p.Arg506X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 248672 control chromosomes (gnomAD). c.1516C>T has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome C; Feldhammer_2009, Hrebicek_2006, Pervaiz_2011, Martins_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: all three classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004817877	SCV005071315	pathogenic	Retinal dystrophy	2020-01-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV004760686	SCV005368424	pathogenic	Retinitis pigmentosa 73	2024-09-24	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM3,PM2_SUP
Fulgent Genetics, Fulgent Genetics	RCV001040598	SCV005675495	pathogenic	Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73	2024-03-05	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000667348	SCV002083320	pathogenic	Mucopolysaccharidosis, MPS-III-C	2020-12-29	no assertion criteria provided	clinical testing
Department of Pediatrics, Taizhou Central Hospital, Taizhou University Hospital	RCV000667348	SCV005045315	pathogenic	Mucopolysaccharidosis, MPS-III-C	2024-02-01	no assertion criteria provided	clinical testing