ClinVar Miner

Submissions for variant NM_001271208.2(NEB):c.2943+1G>A (rs113091511)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000667067 SCV000791460 pathogenic Nemaline myopathy 2 2017-05-19 criteria provided, single submitter clinical testing
Invitae RCV000667067 SCV001206301 pathogenic Nemaline myopathy 2 2019-12-19 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 29 of the NEB gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individuals affected with nemaline myopathy (PMID: 25205138). ClinVar contains an entry for this variant (Variation ID: 551899). 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 RCV001255511 SCV001431944 pathogenic Nemaline myopathy 2020-08-10 criteria provided, single submitter clinical testing Variant summary: NEB c.2943+1G>A 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 4.1e-06 in 246536 control chromosomes. c.2943+1G>A has been reported in the literature in individuals affected with Nemaline Myopathy (example, Lehtokari_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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