Submissions for variant NM_000528.4(MAN2B1):c.2140T>C (p.Trp714Arg)

gnomAD frequency: 0.00002  dbSNP: rs864621993

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206950	SCV001377537	likely pathogenic	Deficiency of alpha-mannosidase	2024-02-25	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 714 of the MAN2B1 protein (p.Trp714Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with alpha-mannosidosis (PMID: 9915946, 22161967). ClinVar contains an entry for this variant (Variation ID: 208284). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MAN2B1 protein function. Experimental studies have shown that this missense change affects MAN2B1 function (PMID: 15035660). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Myriad Genetics, Inc.	RCV000206950	SCV002060027	likely pathogenic	Deficiency of alpha-mannosidase	2021-11-10	criteria provided, single submitter	clinical testing	NM_000528.3(MAN2B1):c.2140T>C(W714R) is a missense variant classified as likely pathogenic in the context of alpha-mannosidosis. W714R has been observed in cases with relevant disease (PMID: 9915946, 22161967). Functional assessments of this variant are available in the literature (PMID: 15035660). Internal structural analysis of the variant is supportive of pathogenicity. W714R has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, NM_000528.3(MAN2B1):c.2140T>C(W714R) is a missense variant that has both functional and internal structural support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000206950	SCV005077519	likely pathogenic	Deficiency of alpha-mannosidase	2024-04-04	criteria provided, single submitter	clinical testing	Variant summary: MAN2B1 c.2140T>C (p.Trp714Arg) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 38, C-terminal (IPR011682) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251456 control chromosomes. c.2140T>C has been reported in the literature in individuals affected with Alpha-Mannosidosis (Berg_1999, Riise_2012). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating defective protein transport and activity (Hansen_2004). ClinVar contains an entry for this variant (Variation ID: 208284). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000206950	SCV005655493	likely pathogenic	Deficiency of alpha-mannosidase	2024-04-05	criteria provided, single submitter	clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000206950	SCV000243993	uncertain significance	Deficiency of alpha-mannosidase	2012-06-07	no assertion criteria provided	literature only
Natera, Inc.	RCV000206950	SCV002086912	likely pathogenic	Deficiency of alpha-mannosidase	2017-06-23	no assertion criteria provided	clinical testing