Submissions for variant NM_001271208.2(NEB):c.3987+1_3987+2delinsTG (rs786204576)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169318	SCV000220647	likely pathogenic	Nemaline myopathy 2	2014-08-27	criteria provided, single submitter	literature only
GeneDx	RCV000493120	SCV000582483	pathogenic	not provided	2015-09-01	criteria provided, single submitter	clinical testing	The c. 3987+1_3987+2delGTinsTG splice site variant in the NEB gene destroys the canonical splice donor site of intron 36. 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.3987+1_3987_2delGTinsTG was previously reported, using alternative nomenclature, in a family with nemaline myopathy, although a second pathogenic variant in NEB was not identified (Lehtokari et al., 2006). The c.3987+1_3987+2delGTinsTG variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, other pathogenic splice site variants in the NEB gene have been reported in the Human Gene Mutation Database in association with nemaline myopathy (Stenson et al., 2014). Therefore, we interpret c.3987+1_3987+2delGTinsTG as a pathogenic variant.
Invitae	RCV000169318	SCV000947380	pathogenic	Nemaline myopathy 2	2018-10-07	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 36 of the NEB gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in combination with another NEB variant in several families affected with nemaline myopathy (PMID: 25205138). ClinVar contains an entry for this variant (Variation ID: 188944). 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.