ClinVar Miner

Submissions for variant NM_000528.4(MAN2B1):c.1230G>C (p.Gln410His)

gnomAD frequency: 0.00001  dbSNP: rs563097824
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498197 SCV000590194 uncertain significance not provided 2017-06-12 criteria provided, single submitter clinical testing The c.1230 G>C variant in the MAN2B1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is observed in 5/16,492 alleles (0.03%) from individuals of South Asian background in the ExAC dataset, with no homozygous control individuals reported (Lek et al., 2016). Splice models predict that c.1230 G>C destroys the natural splice door site of exon 9. However, in the absence of RNA/functional studies, the actual effect of the c.1230 G>C change in this individual is unknown. If c.1230 G>C does not alter splicing, it will result in the Q410H missense change. The Q410H variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret c.1230 G>C as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001273204 SCV003451498 uncertain significance Deficiency of alpha-mannosidase 2022-09-18 criteria provided, single submitter clinical testing This sequence change affects codon 410 of the MAN2B1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MAN2B1 protein. This variant also falls at the last nucleotide of exon 9, which is part of the consensus splice site for this exon. This variant is present in population databases (rs563097824, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with MAN2B1-related conditions. ClinVar contains an entry for this variant (Variation ID: 432466). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Natera, Inc. RCV001273204 SCV001455939 uncertain significance Deficiency of alpha-mannosidase 2020-01-24 no assertion criteria provided clinical testing

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