Submissions for variant NM_001164508.2(NEB):c.3879+1G>A

gnomAD frequency: 0.00001  dbSNP: rs746999970

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000670383	SCV000795228	likely pathogenic	Nemaline myopathy 2	2017-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000670383	SCV001208924	pathogenic	Nemaline myopathy 2	2024-05-02	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 35 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individuals with nemaline myopathy who carry a second pathogenic variant (PMID: 25205138; Invitae). ClinVar contains an entry for this variant (Variation ID: 554705). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265844	SCV002548179	likely pathogenic	Nemaline myopathy	2022-05-06	criteria provided, single submitter	clinical testing	Variant summary: NEB c.3879+1G>A 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: 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 9.8e-06 in 204144 control chromosomes (gnomAD). c.3879+1G>A has been reported in the literature in at least one individual affected with Nemaline Myopathy (Lehtokari_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV003442015	SCV004169104	likely pathogenic	not provided	2023-10-12	criteria provided, single submitter	clinical testing	Reported previously in a patient with nemaline myopathy who also harbored a second NEB variant; however phase was undetermined (Lehtokari et al., 2014); 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 involving coding exons in this gene are frequently reported as pathogenic, regardless of frame prediction (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25205138, 24077912)
Baylor Genetics	RCV003465499	SCV004200091	pathogenic	Arthrogryposis multiplex congenita 6	2024-03-30	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000670383	SCV002077727	pathogenic	Nemaline myopathy 2	2020-12-31	no assertion criteria provided	clinical testing