ClinVar Miner

Submissions for variant NM_000528.4(MAN2B1):c.1383C>G (p.Tyr461Ter) (rs775200333)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169471 SCV000220912 likely pathogenic Deficiency of alpha-mannosidase 2014-11-25 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169471 SCV000697258 pathogenic Deficiency of alpha-mannosidase 2016-08-04 criteria provided, single submitter clinical testing Variant summary: The MAN2B1 c.1383C>G (p.Tyr461X) variant results in a premature termination codon, predicted to cause a truncated or absent MAN2B1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was absent in 17720 control chromosomes, but has been observed in at least one alpha-mannosidosis patient in homozygous state. In addition, one clinical diagnostic laboratory classified this variant as likely pathogenic, and a similar variant, c.1383C>A (p.Y461X), was classified as pathogenic by Emory Genetics. c.1383C>A (p.Y461X) has been reported in multiple alpha-mannosidosis patients (PMID: 22161967). Taken together, this variant is classified as Pathogenic.
Invitae RCV000169471 SCV000936192 pathogenic Deficiency of alpha-mannosidase 2018-12-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr461*) 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 a homozygous individual affected with alpha-mannosidosis (PMID: 17979865). ClinVar contains an entry for this variant (Variation ID: 189068). Loss-of-function variants in MAN2B1 are known to be pathogenic (PMID: 9915946, 22161967). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000169471 SCV000328769 pathogenic Deficiency of alpha-mannosidase 2014-10-03 no assertion criteria provided clinical testing Our laboratory reported dual molecular diagnoses in SCN8A (NM_014191.3, c.647T>G) and MAN2B1 (NM_000528.3, c.2782G>C and c.1383C>G in trans) in one individual with reported features that include delayed motor milestones, delayed speech, intellectual disability, hypotonia, seizure disorder (refractory epilepsy), abnormal movements (dyskinesia), minor dysmorphic features (flat nasal bridge, prominent eyes, full lips), microcephaly, dysphagia, and cortical visual impairment. The c.1383C>G variant in MAN2B1 has been previously reported as disease-causing [PMID 17979865].

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