ClinVar Miner

Submissions for variant NM_006086.4(TUBB3):c.862G>A (p.Glu288Lys)

dbSNP: rs1057521924
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000422965 SCV000525085 pathogenic not provided 2022-02-22 criteria provided, single submitter clinical testing Published functional studies suggest the E288K variant may affect protein processing (Oegema et al., 2015); The majority of missense variants in this gene are considered pathogenic (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28503613, 29261186, 31269740, 26130693, 28677066, 30667171, 32570172, 32901917)
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000824822 SCV000965709 likely pathogenic Complex cortical dysplasia with other brain malformations 1 2014-01-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000422965 SCV001446780 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
3billion RCV000824822 SCV002012258 pathogenic Complex cortical dysplasia with other brain malformations 1 2021-10-02 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogeic with strong evidence and some affected individual has been obsered as de novoo (ClinVar ID: VCV000384329.4, PMID:32570172, PS1 and PS2). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Glu288Ala) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000931842.2, PM5). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.873, 3Cnet: 0.987, PP3). Patient's phenotype is considered compatible with Cortical dysplasia, complex, with other brain malformations 1 (3billion dataset, PP4). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000824822 SCV002819361 pathogenic Complex cortical dysplasia with other brain malformations 1 2022-12-08 criteria provided, single submitter clinical testing Variant summary: TUBB3 c.862G>A (p.Glu288Lys) results in a conservative amino acid change located in the Tubulin/FtsZ, 2-layer sandwich domain (IPR018316) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250300 control chromosomes (gnomAD). c.862G>A has been reported in the literature in multiple individuals affected with Cortical Dysplasia, Complex, With Other Brain Malformations 1, including de novo occurrences (Oegema_2015, Romaniello_2017, Boissel_2017, Accogli_2020, Seo_2020). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports experimental evidence evaluating an impact on protein function and this variant did not incorporate into microtubules (Oegema_2015). Three ClinVar submitters (evaluation after 2014) cite this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000422965 SCV003443672 pathogenic not provided 2022-10-09 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TUBB3 function (PMID: 26130693). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TUBB3 protein function. ClinVar contains an entry for this variant (Variation ID: 384329). This missense change has been observed in individual(s) with cortical malformations (PMID: 26130693, 29261186). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 288 of the TUBB3 protein (p.Glu288Lys).
Diagnostic Laboratory, Strasbourg University Hospital RCV002275022 SCV002562774 pathogenic Abnormal cerebral morphology no assertion criteria provided clinical testing

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