ClinVar Miner

Submissions for variant NM_001271208.2(NEB):c.294+2T>C (rs773952935)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000414510 SCV000341187 pathogenic not provided 2016-05-25 criteria provided, single submitter clinical testing
GeneDx RCV000414510 SCV000491259 likely pathogenic not provided 2016-06-10 criteria provided, single submitter clinical testing The c.294+2T>C variant in the NEB gene has been reported previously in association with nemaline myopathy, in a family where affected individuals were compound heterozygous for the c.294+2T>C variant and another pathogenic variant (Lehtokari et al., 2006). This splice site variant destroys the canonical splice donor site in intron 5. It is predicted to skip 72 amnio acids encoding unique N-terminal domains, and may affect TMOD-binding (Lehtokari et al., 2006). A nearby variant affecting the same canonical splice donor site (c.294+1G>A) has been reported in association with nemaline myopathy (Lehtokari et al., 2006), supporting the importance of this splice donor site. The c.294+2T>C variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.294+2T>C as a likely pathogenic variant.
Invitae RCV000303625 SCV001212115 pathogenic Nemaline myopathy 2 2019-12-03 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 5 of the NEB 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 (rs773952935, ExAC 0.03%). This variant has been observed in individual(s) with nemaline myopathy (PMID: 16917880). 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 g.5468T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 287422). 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). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001192840 SCV001361230 likely pathogenic Nemaline myopathy 2019-04-29 criteria provided, single submitter clinical testing Variant summary: NEB c.294+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: 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 4e-05 in 247568 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in NEB causing Nemaline Myopathy 2 (4e-05 vs 0.0035), allowing no conclusion about variant significance. c.294+2T>C has been reported in the literature in a compound heterozygous individual affected with Nemaline Myopathy 2, who carried another pathogenic variant in trans (Lehtokari 2006). Another variant affecting the same canonical splice donor site (c.294+1G>A) was reported in the same study to result in an in-frame skipping of exon 5 with the deletion of 72 amino acids (i.e. p.Thr27_Pro98del; based on cDNA sequence analysis of mRNA isolated from patient muscle biopsy sample); therefore it was predicted that the variant of interest would cause a similar splicing defect (Lehtokari 2006). Three ClinVar submission from clinical diagnostic laboratories (evaluation after 2014) cite the variant twice as likely pathogenic and once as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Counsyl RCV000303625 SCV000791637 likely pathogenic Nemaline myopathy 2 2017-05-19 no assertion criteria provided clinical testing

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