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NM_006086.4(TUBB3):c.1228G>A (p.Glu410Lys) AND TUBB3-Releated Disorders

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jun 19, 2019
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001267650.9

Allele description [Variation Report for NM_006086.4(TUBB3):c.1228G>A (p.Glu410Lys)]

NM_006086.4(TUBB3):c.1228G>A (p.Glu410Lys)

Gene:
TUBB3:tubulin beta 3 class III [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
16q24.3
Genomic location:
Preferred name:
NM_006086.4(TUBB3):c.1228G>A (p.Glu410Lys)
HGVS:
  • NC_000016.10:g.89935679G>A
  • NG_027810.1:g.18671G>A
  • NM_001197181.2:c.1012G>A
  • NM_006086.4:c.1228G>AMANE SELECT
  • NP_001184110.1:p.Glu338Lys
  • NP_006077.2:p.Glu410Lys
  • NP_006077.2:p.Glu410Lys
  • NC_000016.9:g.90002087G>A
  • NM_006086.3:c.1228G>A
  • Q13509:p.Glu410Lys
Protein change:
E338K; GLU410LYS
Links:
UniProtKB: Q13509#VAR_062763; OMIM: 602661.0005; dbSNP: rs267607165
NCBI 1000 Genomes Browser:
rs267607165
Molecular consequence:
  • NM_001197181.2:c.1012G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_006086.4:c.1228G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
TUBB3-Releated Disorders
Identifiers:

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001445868Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Jun 19, 2019) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV001445868.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This variant has been previously reported as a de novo heterozygous change in patients with hypoplasia of oculomotor nerves, hypoplasia of the corpus callosum, developmental delay, facial weakness, and cyclic vomiting (PMID: 20074521, 23378218, 25559402, 29289389). Functional studies have shown that the c.1228G>A (p.Glu410Lys) variant inhibits axonal transport of vesicles and mitochondria (PMID: 23503589). This variant is in the H12 helix of beta-tubulin and changes the negative charge on the surface of the microtubule, which is important for binding to kinesin superfamily motor proteins (KIFs). The disrupted binding of axonal transport KIFs to microtubules alters the localization of KIFs in neurons and inhibits axon elongation (PMID: 23503589). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.1228G>A (p.Glu410Lys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples showed the mother is negative and the father is negative for this variant, indicating this likely occurred as a de novo event. Based on the available evidence, the c.1228G>A (p.Glu410Lys) variant is classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 26, 2024