ClinVar Miner

Submissions for variant NM_001271208.2(NEB):c.25568A>G (p.Lys8523Arg) (rs201714437)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000733850 SCV000861951 uncertain significance not provided 2018-06-13 criteria provided, single submitter clinical testing
GeneDx RCV000733850 SCV000975633 likely benign not provided 2018-03-15 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Genetic Services Laboratory, University of Chicago RCV000500966 SCV000595950 uncertain significance not specified 2016-07-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000500966 SCV000917875 uncertain significance not specified 2018-06-11 criteria provided, single submitter clinical testing Variant summary: NEB c.25568A>G (p.Lys8523Arg) results in a conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 120734 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in NEB causing Nemaline Myopathy 2 (0.00028 vs 0.0035), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.25568A>G in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000528032 SCV000640758 uncertain significance Nemaline myopathy 2 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 8523 of the NEB protein (p.Lys8523Arg). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs201714437, ExAC 0.04%). This variant has not been reported in the literature in individuals with NEB-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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