Submissions for variant NM_000263.4(NAGLU):c.2T>A (p.Met1Lys)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004783366	SCV005395106	likely pathogenic	Mucopolysaccharidosis, MPS-III-B	2024-09-10	criteria provided, single submitter	clinical testing	Variant summary: NAGLU c.2T>A (p.Met1Lys) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next in frame Met codon occurs at p.157. One of two in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-06 in 1216966 control chromosomes. c.2T>A has been reported in the literature in the presumed compound heterozygous state in at least 1 individual affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) (example, Mangas_2008). Further, a downstream missense c.259G>C (p.Ala87Pro) which occurs prior the next in frame Met has been classified as Pathogenic by our lab, indicating this region of the N-terminus is indispensable for protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 18218046). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as likely pathogenic.