Submissions for variant NM_001164508.2(NEB):c.19626+1G>A

dbSNP: rs756352186

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000853237	SCV000996049	likely pathogenic	Nemaline myopathy 2	2016-10-03	criteria provided, single submitter	clinical testing	This canonical splice donor variant is predicted to alter the function of the protein. This variant was found in only one individual in the Exome Aggregation Consortium (ExAC) database. Thus, it is presumed to be rare. The genomic position is highly conserved and in silico splicing algorithms predict the variant alters splicing mechanisms. Although this particular variant is unreported in the literature, splice site variants are well established as disease causing in the NEB gene (PMID: 25205138). Based on the available evidence, the c.19626+1G>A variant is classified as a likely pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797801	SCV002041628	likely pathogenic	Nemaline myopathy	2021-11-05	criteria provided, single submitter	clinical testing	Variant summary: NEB c.19626+1G>A alters a conserved nucleotide 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 243710 control chromosomes (gnomAD). c.19626+1G>A has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Nemaline Myopathy 2 (example, Farnaes_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000853237	SCV002249785	likely pathogenic	Nemaline myopathy 2	2023-01-03	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: 691986). Disruption of this splice site has been observed in individual(s) with NEB-related conditions (PMID: 29644095). This variant is present in population databases (rs756352186, gnomAD 0.003%). This sequence change affects a donor splice site in intron 126 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).
GeneDx	RCV004726704	SCV005333004	likely pathogenic	not provided	2024-03-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Deletions and loss of function variants involving coding exons of this gene are a known mechanism of disease (HGMD); This variant is associated with the following publications: (PMID: 16199547, 29644095, 25205138, 34645491)