ClinVar Miner

Submissions for variant NM_000528.4(MAN2B1):c.418C>T (p.Arg140Ter) (rs370803545)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,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
Integrated Genetics/Laboratory Corporation of America 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 2019-10-02 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. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with mannosidosis (PMID: 22161967, 26048034). ClinVar contains an entry for this variant (Variation ID: 328281). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in MAN2B1 are known to be pathogenic (PMID: 9915946, 22161967). For these reasons, this variant has been classified as Pathogenic.

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