Submissions for variant NM_001164508.2(NEB):c.3987+1_3987+2delinsTG

dbSNP: rs786204576

Total submissions: 6

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169318	SCV000947380	pathogenic	Nemaline myopathy 2	2024-12-05	criteria provided, single submitter	clinical testing	This sequence change affects a splice site in intron 36 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). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. Disruption of this splice site has been observed in individuals with nemaline myopathy (PMID: 25205138). ClinVar contains an entry for this variant (Variation ID: 188944). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553644	SCV001774579	pathogenic	Nemaline myopathy	2022-07-25	criteria provided, single submitter	clinical testing	Variant summary: NEB c.3987+1_3987+2delinsTG 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: 4/4 predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele, which consists of two single nucleotide changes in cis (c.3987+1G>T and c.3987+2T>G), was found at a frequency of 1.8e-05 in 280626 control chromosomes (gnomAD v2.1). The variant c.3987+1_3987+2delinsTG (also described as c.3987+1_3987+2inv) has been reported in the literature in multiple families / individuals affected with Nemaline Myopathy 2 (Lehtokari_2006, Lehtokari_2014, Ravenscroft_2020). These data indicate that the variant is likely to be associated with the disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Another variant affecting the same splice site was also reported in multiple affected individuals (Lehtokari_2014). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003474905	SCV004200197	pathogenic	Arthrogryposis multiplex congenita 6	2024-03-16	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005016513	SCV005652529	pathogenic	Nemaline myopathy 2; Arthrogryposis multiplex congenita 6	2024-05-03	criteria provided, single submitter	clinical testing