Submissions for variant NM_000528.4(MAN2B1):c.418C>T (p.Arg140Ter)

dbSNP: rs370803545

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000384198	SCV000410811	likely pathogenic	Deficiency of alpha-mannosidase	2017-04-27	criteria provided, single submitter	clinical testing	The MAN2B1 c.418C>T (p.Arg140Ter) variant is a stop-gained variant and has been reported in at least two studies in which it is found in at least three individuals with alpha-mannosidosis including one in a homozygous state and two in a compound heterozygous state with a missense variant on the second allele (Stensland H et al. 2012; Borgwardt et al. 2015). Control data are unavailable for this variant and it is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Due to the potential impact of stop-gained variants and evidence from the literature, the p.Arg140Ter variant is classified as likely pathogenic for alpha-mannosidosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Counsyl	RCV000384198	SCV000486962	pathogenic	Deficiency of alpha-mannosidase	2016-09-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000384198	SCV000917600	pathogenic	Deficiency of alpha-mannosidase	2018-11-26	criteria provided, single submitter	clinical testing	Variant summary: MAN2B1 c.418C>T (p.Arg140X) 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. The variant allele was found at a frequency of 1.7e-05 in 240946 control chromosomes (gnomAD). The variant, c.418C>T, has been reported in the literature in individuals affected with Alpha-Mannosidosis, in both compound heterozygotes and one homozygote (Borgwardt_2015, RiseStensland_2012). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000384198	SCV000965808	pathogenic	Deficiency of alpha-mannosidase		criteria provided, single submitter	clinical testing
Invitae	RCV000384198	SCV001378221	pathogenic	Deficiency of alpha-mannosidase	2023-11-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg140*) in the MAN2B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MAN2B1 are known to be pathogenic (PMID: 9915946, 22161967). This variant is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with mannosidosis (PMID: 22161967, 26048034). ClinVar contains an entry for this variant (Variation ID: 328281). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000384198	SCV002014514	pathogenic	Deficiency of alpha-mannosidase	2021-09-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000384198	SCV004191842	pathogenic	Deficiency of alpha-mannosidase	2023-10-22	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000384198	SCV002086944	pathogenic	Deficiency of alpha-mannosidase	2020-10-19	no assertion criteria provided	clinical testing