Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| EGL Genetic Diagnostics, |
RCV000790650 | SCV000225853 | pathogenic | not provided | 2013-11-14 | criteria provided, single submitter | clinical testing | |
| Counsyl | RCV000174538 | SCV000799429 | pathogenic | Nemaline myopathy 2 | 2018-04-18 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000174538 | SCV000956532 | pathogenic | Nemaline myopathy 2 | 2018-10-23 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 13 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). This variant has been observed in combination with another NEB variant in several individuals and families affected with nemaline myopathy (PMID: PMID: 23572184, 25079567, 25205138). ClinVar contains an entry for this variant (Variation ID: 95104). 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. |
| Integrated Genetics/Laboratory Corporation of America | RCV001174709 | SCV001337975 | pathogenic | Nemaline myopathy | 2020-01-23 | criteria provided, single submitter | clinical testing | Variant summary: NEB c.1152+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 1.8e-05 in 219184 control chromosomes (gnomAD). c.1152+1G>A has been reported in the literature in individuals affected with Nemaline Myopathy (e.g. de Winter_2013, Lehtokari_2014). These data indicate that the variant is likely to be associated with disease. Muscle from a patient with the variant exhibited relative deficiency of nebulin protein and lower calcium-sensitivity of force generation and maximal active tension compared to controls (de Winter_2013). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |