ClinVar Miner

Submissions for variant NM_006086.4(TUBB3):c.785G>A (p.Arg262His) (rs864321716)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519071 SCV000616910 pathogenic not provided 2018-10-15 criteria provided, single submitter clinical testing The R262H variant in the TUBB3 gene has been reported previously in three individuals from 2 families with severe CFEOM3 who had facial weakness, MRI abnormalities, developmental delay, and neuropathy (Tischfield et al., 2010). In vitro functional studies demonstrated that the presence of the R262H variant causes reduced binding of kinesin and non-motor proteins and exhibits altered polymerization dynamics (Minoura et al., 2016). The R262H variant is not observed in large population cohorts (Lek et al., 2016). The R262H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species. Therefore, the presence of R262H is consistent with the diagnosis of a TUBB3-related disorder in this individual.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000203607 SCV000965751 likely pathogenic Fibrosis of extraocular muscles, congenital, 3a, with or without extraocular involvement 2015-01-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000519071 SCV001447090 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000519071 SCV001449592 likely pathogenic not provided 2015-06-29 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001270742 SCV001451490 pathogenic TUBB3-related tubulinopathy 2019-05-01 criteria provided, single submitter clinical testing The TUBB3 c.785G>A (p.Arg262His) variant is a missense variant that has been reported in two studies, in which it is found in a de novo heterozygous state in three individuals with a severe form of congenital fibrosis of the extraocular muscles (CFEOM). Another variant at the same amino acid position has also been reported in 11 families with a milder form of CFEOM (Tischfield et al. 2010; MacKinnon et al. 2014). The p.Arg262His variant was absent from 1700 control chromosomes and is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Functional studies in yeast demonstrate that compared to wild-type microtubules, the p.Arg262His microtubules have prolonged growth events, longer astral microtubules, and an altered rate of polymerization and depolymerization. In vivo assays further demonstrate that p.Arg262His leads to significantly reduced kinesin interaction on microtubules and modifies the microtubule dynamics at both filament ends (Tischfield et al. 2010; Ti et al. 2016; Minoura et al. 2016). In vitro and in vivo transfection of variant TUBB3 resulted in reduced axon growth; this phenotype was rescued by co-transfection of a modified kinesin (Minoura et al. 2016). The p.Arg262His variant is predicted to abolish the hydrogen bond of the H8-S7 loop of b-tubulin and affect the tertiary protein structure and motor protein interactions with microtubules (Tischfield et al. 2010). Based on the collective evidence and application of the ACMG criteria, the p.Arg262His variant is classified as pathogenic for TUBB3-related tubulinopathy.
Baylor Genetics RCV000203607 SCV001525138 pathogenic Fibrosis of extraocular muscles, congenital, 3a, with or without extraocular involvement 2019-09-27 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
GeneReviews RCV000203607 SCV000258987 pathogenic Fibrosis of extraocular muscles, congenital, 3a, with or without extraocular involvement 2016-01-14 no assertion criteria provided literature only

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