ClinVar Miner

Submissions for variant NM_001164508.2(NEB):c.11333T>C (p.Ile3778Thr)

gnomAD frequency: 0.00009  dbSNP: rs200270156
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000501113 SCV000595953 uncertain significance not specified 2016-08-26 criteria provided, single submitter clinical testing
Invitae RCV000536707 SCV000640501 uncertain significance Nemaline myopathy 2 2021-11-24 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 3778 of the NEB protein (p.Ile3778Thr). This variant is present in population databases (rs200270156, gnomAD 0.02%). This missense change has been observed in individual(s) with nemaline myopathy (PMID: 27168972). ClinVar contains an entry for this variant (Variation ID: 435964). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000536707 SCV000789031 uncertain significance Nemaline myopathy 2 2016-12-27 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000536707 SCV001289368 uncertain significance Nemaline myopathy 2 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx RCV001567425 SCV001791105 uncertain significance not provided 2019-11-15 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed with a missense variant on the opposite allele (in trans) in an aborted fetus with IUGR, joint contractures, mild hydrocephalus, and decreased fetal movements; these variants were also observed in a previous similarly affected fetus of the parents (Pangalos et al., 2016); This variant is associated with the following publications: (PMID: 27168972)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001844179 SCV002103621 likely pathogenic Nemaline myopathy 2022-02-24 criteria provided, single submitter clinical testing Variant summary: NEB c.11333T>C (p.Ile3778Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 249004 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in NEB causing Nemaline Myopathy 2 (8.4e-05 vs 0.0035), allowing no conclusion about variant significance. c.11333T>C has been reported in the literature in multiple individuals affected with Nemaline Myopathy 2, including two affected fetal compound heterozygotes diagnosed as Nemaline myopathy (example, Pangalos_2016) and 2 homozygotes who had a co-existing diagnosis of combined oxidative phosphorylation deficiency 11 (homozygosity for variation in a different gene, RMND1) and Nemaline myopathy 2 (example, Sallevelt_2021). 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. Six ClinVar submitters have assessed the variant since 2014: all have classified the variant as of uncertain significance. Some submitters cite overlapping but not identical evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Natera, Inc. RCV000536707 SCV001459402 uncertain significance Nemaline myopathy 2 2020-09-16 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.