Submissions for variant NM_001271208.2(NEB):c.22695+2T>C (rs200449517)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521210	SCV000619698	likely pathogenic	not provided	2017-08-11	criteria provided, single submitter	clinical testing	The c.22695+2T>C 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 155. 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.22695+2T>C variant is observed in 14/66506 (0.02%) alleles from individuals of non-Finnish European background, in the ExAC dataset (Lek et al., 2016). We interpret c.22695+2T>C as a likely pathogenic variant.
Counsyl	RCV000666422	SCV000790711	likely pathogenic	Nemaline myopathy 2	2017-04-05	criteria provided, single submitter	clinical testing
Invitae	RCV000666422	SCV000830524	likely pathogenic	Nemaline myopathy 2	2018-12-12	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 155 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 (rs200449517, ExAC 0.02%). This variant has not been reported in the literature in individuals with NEB-related disease. ClinVar contains an entry for this variant (Variation ID: 451052). 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.
Illumina Clinical Services Laboratory,Illumina	RCV000666422	SCV000915864	uncertain significance	Nemaline myopathy 2	2018-10-30	criteria provided, single submitter	clinical testing	The NEB c.17487+2T>C variant, which corresponds to c.22695+2T>C in the transcript NM_001271208.1, occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. A literature search was performed for the gene and cDNA change. No publications were found through this search. The c.17487+2T>C variant is reported at a frequency of 0.000211 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the potential impact of splice variants and the lack of clarifying evidence, the c.17487+2T>C variant is classified as of uncertain significance but suspicious for pathogenicity for nemaline myopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.