ClinVar Miner

Submissions for variant NM_000528.4(MAN2B1):c.1830+1G>C (rs80338677)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000020364 SCV000220221 pathogenic Deficiency of alpha-mannosidase 2014-04-03 criteria provided, single submitter literature only
Ambry Genetics RCV000622767 SCV000742222 pathogenic Inborn genetic diseases 2017-05-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000020364 SCV001364017 pathogenic Deficiency of alpha-mannosidase 2019-11-25 criteria provided, single submitter clinical testing Variant summary: MAN2B1 c.1830+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9.3e-05 in 248630 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MAN2B1 causing Alpha-Mannosidosis (9.3e-05 vs 0.0016). c.1830+1G>C has been reported in the literature as one of the most common disease causing variants in multiple individuals affected with Alpha-Mannosidosis (example, Riise Stensland_2012, Berg_1999). These data indicate that the variant is very likely to be associated with disease. No experimental evidence demonstrating an impact on protein function were ascertained within the context of this evaluation. One clinical diagnostic laboratory has 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.
Invitae RCV000020364 SCV001588917 pathogenic Deficiency of alpha-mannosidase 2020-10-14 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 14 of the MAN2B1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs80338677, ExAC 0.02%). This variant has been observed in individual(s) with mannosidosis (PMID: 9915946, 26048034). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS14+1G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 21207). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MAN2B1 are known to be pathogenic (PMID: 9915946, 22161967). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001564933 SCV001788179 pathogenic not provided 2021-03-15 criteria provided, single submitter clinical testing Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 31980526, 9915946, 22161967, 25525159)
GeneReviews RCV000020364 SCV000040751 pathologic Deficiency of alpha-mannosidase 2012-05-03 no assertion criteria provided curation Converted during submission to Pathogenic.
OMIM RCV000020364 SCV000056374 pathogenic Deficiency of alpha-mannosidase 2012-03-01 no assertion criteria provided literature only
Natera, Inc. RCV000020364 SCV001454353 pathogenic Deficiency of alpha-mannosidase 2020-09-16 no assertion criteria provided clinical testing

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