Submissions for variant NM_001164508.2(NEB):c.294+2T>C

gnomAD frequency: 0.00001  dbSNP: rs773952935

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000414510	SCV000341187	pathogenic	not provided	2016-05-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000414510	SCV000491259	likely pathogenic	not provided	2023-07-27	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); This variant is associated with the following publications: (PMID: 16917880, 25525159, 25205138)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000303625	SCV001212115	pathogenic	Nemaline myopathy 2	2024-10-22	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 5 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). This variant is present in population databases (rs773952935, gnomAD 0.03%). Disruption of this splice site has been observed in individual(s) with nemaline myopathy (PMID: 16917880). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as g.5468T>C. ClinVar contains an entry for this variant (Variation ID: 287422). 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	RCV001192840	SCV001361230	pathogenic	Nemaline myopathy	2024-09-09	criteria provided, single submitter	clinical testing	Variant summary: NEB c.294+2T>C 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of NEB function. 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 4e-05 in 247568 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in NEB causing Nemaline Myopathy 2 (4e-05 vs 0.0035), allowing no conclusion about variant significance. c.294+2T>C has been reported in the literature in a compound heterozygous individual affected with Nemaline Myopathy 2, who carried another pathogenic variant in trans (Lehtokari 2006). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25525159, 25205138, 16917880). ClinVar contains an entry for this variant (Variation ID: 287422). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003469243	SCV004200210	pathogenic	Arthrogryposis multiplex congenita 6	2024-02-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000414510	SCV004238306	likely pathogenic	not provided	2023-03-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000303625	SCV000791637	likely pathogenic	Nemaline myopathy 2	2017-05-19	no assertion criteria provided	clinical testing