Submissions for variant NM_002076.4(GNS):c.714G>A (p.Trp238Ter)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002302492	SCV002598724	likely pathogenic	Mucopolysaccharidosis, MPS-III-D	2022-09-01	criteria provided, single submitter	clinical testing	Variant summary: GNS c.714G>A (p.Trp238X) 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 reported in affected individuals (HGMD). The variant was absent in 251484 control chromosomes (gnomAD). To our knowledge, no occurrence of c.714G>A in individuals affected with Mucopolysaccharidosis Type IIID (Sanfilippo Syndrome D) and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002302492	SCV004533090	pathogenic	Mucopolysaccharidosis, MPS-III-D	2023-05-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1722378). This variant has not been reported in the literature in individuals affected with GNS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp238*) in the GNS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GNS are known to be pathogenic (PMID: 20232353).