Submissions for variant NM_000263.4(NAGLU):c.736G>C (p.Ala246Pro)

dbSNP: rs1415169705

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323906	SCV004030135	uncertain significance	not specified	2023-07-27	criteria provided, single submitter	clinical testing	Variant summary: NAGLU c.736G>C (p.Ala246Pro) results in a non-conservative amino acid change located in the Alpha-N-acetylglucosaminidase, tim-barrel domain (IPR024733) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250374 control chromosomes. c.736G>C has been reported in the literature in at least one heterozygous individual affected with severe Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B), with a reportedly unknown variant in the second allele (e.g. Beesley_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 12% of normal alpha-N-acetylglucosaminidase enzyme activity in vitro (e.g. Beesley_2005). The following publication has been ascertained in the context of this evaluation (PMID: 16151907). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001573044	SCV001798341	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001573044	SCV001917694	uncertain significance	not provided		no assertion criteria provided	clinical testing