Submissions for variant NM_152419.3(HGSNAT):c.739del (p.Arg247fs)

dbSNP: rs1085307880

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489181	SCV000577561	pathogenic	not provided	2020-11-04	criteria provided, single submitter	clinical testing	Frameshift 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: 17397050, 19479962, 31228227)
Counsyl	RCV000666153	SCV000790398	pathogenic	Mucopolysaccharidosis, MPS-III-C	2017-03-17	criteria provided, single submitter	clinical testing
Invitae	RCV000691847	SCV000819643	pathogenic	Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg247Glyfs*29) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type IIIC (PMID: 17397050, 19479962). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 426971). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155215	SCV003844666	pathogenic	Sanfilippo syndrome	2023-02-13	criteria provided, single submitter	clinical testing	Variant summary: HGSNAT c.739delA (p.Arg247GlyfsX29) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 220554 control chromosomes (gnomAD). c.739delA has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome C) (Examples: Fedele_2007 and Feldhammer_2009). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.