ClinVar Miner

Submissions for variant NM_001271208.2(NEB):c.3255+1G>A (rs375628303)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519006 SCV000617717 pathogenic not provided 2016-01-11 criteria provided, single submitter clinical testing The c.3255+1 G>A variant in the NEB gene has been reported in association with nemaline myopathy (Lehtokari et al., 2006; Lehtokari et al., 2014). This splice site variant in the destroys the canonical splice donor site in intron 32. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation
Invitae RCV000536181 SCV000640776 pathogenic Nemaline myopathy 2 2019-08-20 criteria provided, single submitter clinical testing This sequence change affects donor splice site in intron 32 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 (rs375628303, ExAC 0.02%). This variant has been reported in individuals affected with nemaline myopathy (PMID: 25205138, 16917880). This variant is also known as g.53437G>A in the literature. 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.
Institute of Human Genetics,Klinikum rechts der Isar RCV000536181 SCV001149847 pathogenic Nemaline myopathy 2 2018-02-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001192838 SCV001361226 pathogenic Nemaline myopathy 2019-01-24 criteria provided, single submitter clinical testing Variant summary: NEB c.3255+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein. Several computational tools predict a significant impact on normal splicing: five predict the variant abolishes a 5' splicing donor site. At least one publication reported experimental evidence that this variant affects mRNA splicing, demonstrating skipping of exon 32, predicted to result in the deletion of 36 amino acid leading to impaired tropomyosin-binding (Lehtokari 2006). The variant allele was found at a frequency of 1.1e-05 in 275720 control chromosomes (gnomAD). c.3255+1G>A has been reported in the literature in compound heterozygous individuals affected with Nemaline Myopathy 2 (Lehtokari 2006, Lehtokari 2014). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl RCV000536181 SCV000791647 pathogenic Nemaline myopathy 2 2017-05-19 no assertion criteria provided clinical testing

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