Submissions for variant NM_000528.4(MAN2B1):c.2945C>T (p.Pro982Leu)

gnomAD frequency: 0.00002  dbSNP: rs376856949

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001919379	SCV002191877	uncertain significance	Deficiency of alpha-mannosidase	2021-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 982 of the MAN2B1 protein (p.Pro982Leu). This variant is present in population databases (rs376856949, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with MAN2B1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235623	SCV003934622	uncertain significance	not specified	2023-05-22	criteria provided, single submitter	clinical testing	Variant summary: MAN2B1 c.2945C>T (p.Pro982Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251430 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2945C>T has been reported in the literature in at-least one individual affected Autism spectrum disorder (examples: Koire_2021 and Turner_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Alpha-Mannosidosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34011629, 28714951, 27149842, 31785789). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.