ClinVar Miner

Submissions for variant NM_001164508.2(NEB):c.19102-10_19102-4del

dbSNP: rs1577576425
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mendelics RCV000986837 SCV001135976 likely pathogenic Nemaline myopathy 2 2019-05-28 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000986837 SCV003017147 uncertain significance Nemaline myopathy 2 2023-05-08 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 801769). This variant has been observed in individual(s) with NEB-related conditions (PMID: 25205138). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 122 of the NEB gene. It does not directly change the encoded amino acid sequence of the NEB protein.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000986837 SCV003922353 uncertain significance Nemaline myopathy 2 2023-05-02 criteria provided, single submitter curation The heterozygous c.19102-10_19102-4del variant in NEB was identified by our study, in the compound heterozygous state with a variant of uncertain significance (NC_000002.12:g.151548343C>T), in one individual with nemaline myopathy. Trio exome analysis revealed that this variant was in trans with a variant of uncertain significance (NC_000002.12:g.151548343C>T). The c.19102-10_19102-4del variant in NEB has been previously reported in one individual with nemaline myopathy 2 (PMID: 25205138). This variant is absent from population databases. This variant has also been reported in ClinVar (Variation ID: 801769) and has been interpreted as likely pathogenic by Mendelics. The affected individual previously reported was a compound heterozygote who carried a likely pathogenic variant in unknown phase ((PMID: 25205138, ClinVar Variation ID: 557505), and the patient identified by our study was a compound heterozygote who carried a variant of uncertain significance in trans (NC_000002.12:g.151548343C>T), which increases the likelihood that the c.19102-10_19102-4del variant is pathogenic. This variant is located in the 3' splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the c.19102-10_19102-4del variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PM3_Supporting, PP3 (Richards 2015).

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