ClinVar Miner

Submissions for variant NM_001164508.2(NEB):c.18472-1G>C

gnomAD frequency: 0.00003  dbSNP: rs1203257517
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001377790 SCV001575213 likely pathogenic Nemaline myopathy 2 2023-09-21 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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: 1066715). This variant has not been reported in the literature in individuals affected with NEB-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 117 of the NEB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002307737 SCV002600405 likely pathogenic Nemaline myopathy 2022-10-10 criteria provided, single submitter clinical testing Variant summary: NEB c.18472-1G>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 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.7e-05 in 150900 control chromosomes (gnomAD v3.1, genomes dataset). To our knowledge, no occurrence of c.18472-1G>C in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002504630 SCV002806862 likely pathogenic Nemaline myopathy 2; Arthrogryposis multiplex congenita 6 2022-04-27 criteria provided, single submitter clinical testing
Baylor Genetics RCV003473906 SCV004200215 likely pathogenic Arthrogryposis multiplex congenita 6 2023-07-11 criteria provided, single submitter clinical testing
Natera, Inc. RCV001377790 SCV002076962 likely pathogenic Nemaline myopathy 2 2020-08-17 no assertion criteria provided clinical testing

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