ClinVar Miner

Submissions for variant NM_001164508.2(NEB):c.20577+2T>C

gnomAD frequency: 0.00001  dbSNP: rs1185654671
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000669880 SCV000794676 likely pathogenic Nemaline myopathy 2 2017-10-11 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000669880 SCV001575643 likely pathogenic Nemaline myopathy 2 2021-03-24 criteria provided, single submitter clinical testing 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). 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. This variant has not been reported in the literature in individuals with NEB-related conditions. ClinVar contains an entry for this variant (Variation ID: 554275). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 135 of the NEB gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003235340 SCV003934765 likely pathogenic Nemaline myopathy 2023-05-30 criteria provided, single submitter clinical testing Variant summary: NEB c.20577+2T>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: One predicts the variant has no significant impact on splicing, and three predict it abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 239380 control chromosomes (gnomAD). To our knowledge, no occurrence of c.20577+2T>C in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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