ClinVar Miner

Submissions for variant NM_000528.4(MAN2B1):c.599A>T (p.His200Leu)

dbSNP: rs864621978
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000206976 SCV005836953 likely pathogenic Deficiency of alpha-mannosidase 2024-03-17 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 200 of the MAN2B1 protein (p.His200Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with alpha mannosidosis (PMID: 15712269, 22161967, 26048034). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 208256). 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: 15712269). This variant disrupts the p.His200 amino acid residue in MAN2B1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16919251, 21505070, 22161967, 26048034). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000206976 SCV000243962 uncertain significance Deficiency of alpha-mannosidase 2012-06-07 no assertion criteria provided literature only

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