Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000674087 | SCV000799361 | likely pathogenic | Nemaline myopathy 2 | 2018-04-17 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001194218 | SCV001363577 | likely pathogenic | Nemaline myopathy | 2019-01-14 | criteria provided, single submitter | clinical testing | Variant summary: NEB c.20659C>T (p.Arg6887X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.21076C>T (p.Arg7026X), c.24407_24410dupTGTT (p.Leu8137fsX18), c.24559C>T (p.Arg8187X)). The variant allele was found at a frequency of 7.2e-06 in 275868 control chromosomes (gnomAD). c.20659C>T has been reported in the literature in a family affected with Nemaline Myopathy 2 (Lehtokari 2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Labcorp Genetics |
RCV000674087 | SCV001591073 | pathogenic | Nemaline myopathy 2 | 2022-02-24 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg6887*) in the NEB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). This variant is present in population databases (rs749452641, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with nemaline myopathy (PMID: 25205138). ClinVar contains an entry for this variant (Variation ID: 557888). 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. |
| Ambry Genetics | RCV003243248 | SCV003965386 | pathogenic | Inborn genetic diseases | 2023-03-22 | criteria provided, single submitter | clinical testing | The c.15556C>T (p.R5186*) alteration, located in exon 109 (coding exon 107) of the NEB gene, consists of a C to T substitution at nucleotide position 15556. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 5186. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.001% (2/279302) total alleles studied. The highest observed frequency was 0.005% (1/19474) of East Asian alleles. Based on the available evidence, this alteration is classified as pathogenic. |
| Gene |
RCV003325512 | SCV004032029 | pathogenic | not provided | 2023-08-29 | criteria provided, single submitter | clinical testing | Reported previously with another NEB variant (phase unknown) in an family with severe nemaline myopathy (Lehtokari et al., 2014); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 30467404, 25205138) |
| Baylor Genetics | RCV003472164 | SCV004200128 | pathogenic | Arthrogryposis multiplex congenita 6 | 2023-09-07 | criteria provided, single submitter | clinical testing |