ClinVar Miner

Submissions for variant NM_001271208.2(NEB):c.18862G>A (p.Val6288Ile) (rs201886728)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724505 SCV000233230 uncertain significance not provided 2015-02-09 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000297544 SCV000416895 uncertain significance Nemaline Myopathy, Recessive 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000724505 SCV000513918 uncertain significance not provided 2017-09-25 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NEB gene. The V6288I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V6288I variant was not observed with any significant frequency in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, but the 1000 Genomes Project reports V6288I was observed in 1/204 (0.5%) alleles from individuals of Sri Lankan background and in 1/208 (0.5%) alleles from individuals of Puerto Rican background. The V6288I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000540531 SCV000640633 uncertain significance Nemaline myopathy 2 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 6288 of the NEB protein (p.Val6288Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs201886728, ExAC 0.05%). This variant has not been reported in the literature in individuals with NEB-related disease. ClinVar contains an entry for this variant (Variation ID: 199223). 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: "Tolerated"; 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.

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