Submissions for variant NM_001164508.2(NEB):c.22590+2T>C

gnomAD frequency: 0.00009  dbSNP: rs200449517

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521210	SCV000619698	likely pathogenic	not provided	2024-02-22	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 in this gene are frequently reported as pathogenic, regardless of frame prediction (HGMD); Has not been previously published as pathogenic or benign to our knowledge
Counsyl	RCV000666422	SCV000790711	likely pathogenic	Nemaline myopathy 2	2017-04-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000666422	SCV000830524	likely pathogenic	Nemaline myopathy 2	2024-01-08	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. 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 (rs200449517, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with NEB-related conditions. 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. 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 Laboratory Services, 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.
CeGaT Center for Human Genetics Tuebingen	RCV000521210	SCV001152434	likely pathogenic	not provided	2017-09-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000521210	SCV002017929	likely pathogenic	not provided	2020-10-02	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000666422	SCV002557409	likely pathogenic	Nemaline myopathy 2	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with arthrogryposis multiplex congenita 6 (MIM#619334) and nemaline myopathy 2 (MIM#256030). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (OMIM). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (28 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0705 - No comparable canonical splice variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported once as a VUS, but multiple times as likely pathogenic but with limited clinical information. One individual had progressive muscle weakness and foot drop with a variant of uncertain significance in trans (ClinVar, personal communication). It has also been observed in a cohort with retinopathy (PMID: 28132693). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282198	SCV002572333	likely pathogenic	Nemaline myopathy	2024-01-11	criteria provided, single submitter	clinical testing	Variant summary: NEB c.22695+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. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site, and one predicts the variant has no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9.3e-05 in 248252 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NEB causing Nemaline Myopathy 2 (9.3e-05 vs 0.0035), allowing no conclusion about variant significance. c.22695+2T>C has been reported in the literature in an individual affected with simplex Retinitis Pigmentosa without any familial history of Nemaline Myopathy and who did not have a reported second pathogenic variant (Arno_2017). This report does not provide unequivocal conclusions about association of the variant with Nemaline Myopathy 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28132693). ClinVar contains an entry for this variant (Variation ID: 451052). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003470655	SCV004200182	uncertain significance	Arthrogryposis multiplex congenita 6	2023-08-09	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000666422	SCV001463281	likely pathogenic	Nemaline myopathy 2	2020-09-16	no assertion criteria provided	clinical testing