Submissions for variant NM_001271208.2(NEB):c.24219+1G>A (rs755239192)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000387492	SCV000329654	pathogenic	not provided	2015-09-10	criteria provided, single submitter	clinical testing	The c.24219+1G>A pathogenic variant in the NEB gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice donor site in intron 170. 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. The c.24219+1G>A variant was not observed in approximately 2300 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.24219+1G>A as a pathogenic variant.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000625834	SCV000746397	pathogenic	Nemaline myopathy 2	2017-12-03	criteria provided, single submitter	clinical testing
Counsyl	RCV000625834	SCV000790290	likely pathogenic	Nemaline myopathy 2	2017-03-09	criteria provided, single submitter	clinical testing
Invitae	RCV000625834	SCV001209384	likely pathogenic	Nemaline myopathy 2	2019-12-13	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 170 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 (rs755239192, ExAC 0.01%). This variant has not been reported in the literature in individuals with NEB-related conditions. ClinVar contains an entry for this variant (Variation ID: 279977). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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). 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.