ClinVar Miner

Submissions for variant NM_001164508.2(NEB):c.3255+2dup

gnomAD frequency: 0.00001  dbSNP: rs1276026682
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000667134 SCV000791537 uncertain significance Nemaline myopathy 2 2017-05-19 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000667134 SCV000827806 uncertain significance Nemaline myopathy 2 2021-08-26 criteria provided, single submitter clinical testing This sequence change falls in intron 32 of the NEB gene. It does not directly change the encoded amino acid sequence of the NEB protein. It affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with nemaline myopathy (PMID: 25205138). ClinVar contains an entry for this variant (Variation ID: 551957). 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 disrupt the consensus 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.
Baylor Genetics RCV003465464 SCV004200179 likely pathogenic Arthrogryposis multiplex congenita 6 2024-02-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003994073 SCV004813830 uncertain significance not specified 2024-02-29 criteria provided, single submitter clinical testing Variant summary: NEB c.3255+2dupT alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 247968 control chromosomes. c.3255+2dupT has been reported in the literature at a homozygous state in at-least one individual affected with Nemaline Myopathy (example, Lehtokari_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25205138). ClinVar contains an entry for this variant (Variation ID: 551957). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
GeneDx RCV004721536 SCV005327140 pathogenic not provided 2024-03-14 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25205138)

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