NM_006086.4(TUBB3):c.763G>A (p.Val255Ile) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Sep 9, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000412886.7

Allele description [Variation Report for NM_006086.4(TUBB3):c.763G>A (p.Val255Ile)]

NM_006086.4(TUBB3):c.763G>A (p.Val255Ile)

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.763G>A (p.Val255Ile)

HGVS:

NC_000016.10:g.89935214G>A
NG_027810.1:g.18206G>A
NM_001197181.2:c.547G>A
NM_006086.4:c.763G>AMANE SELECT
NP_001184110.1:p.Val183Ile
NP_006077.2:p.Val255Ile
NC_000016.9:g.90001622G>A
NM_006086.3:c.763G>A

Protein change:

V183I

Links:

dbSNP: rs1057517908

NCBI 1000 Genomes Browser:

rs1057517908

Molecular consequence:

NM_001197181.2:c.547G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_006086.4:c.763G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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Homo sapiens ABCG4 gene, exon 4
Homo sapiens ABCG4 gene, exon 4
gi|20135826|emb|AJ308241.1|

Nucleotide
cytochrome c oxidase subunit I, partial (mitochondrion) [Hygophum hygomii]
cytochrome c oxidase subunit I, partial (mitochondrion) [Hygophum hygomii]
gi|2624566178|gb|WPM49146.1|

Protein
Homo sapiens dehydrogenase/reductase 3 (DHRS3), transcript variant 3, mRNA
Homo sapiens dehydrogenase/reductase 3 (DHRS3), transcript variant 3, mRNA
gi|1675031440|ref|NM_001324370.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000491036	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely pathogenic (Oct 12, 2016)	germline	clinical testing	Citation Link,
SCV001808416	Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus	no assertion criteria provided	Likely pathogenic	germline	clinical testing
SCV001958980	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely pathogenic	germline	clinical testing
SCV003305072	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 9, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34863918, 28492532

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genome-wide variant calling in reanalysis of exome sequencing data uncovered a pathogenic TUBB3 variant.

de Boer E, Yaldiz B, Denommé-Pichon AS, Matalonga L, Laurie S; Solve-RD SNV-indel working group.; Solve-RD-DITF-ITHACA..

Eur J Med Genet. 2022 Jan;65(1):104402. doi: 10.1016/j.ejmg.2021.104402. Epub 2021 Dec 1.

PubMed [citation]

PMID:: 34863918

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From GeneDx, SCV000491036.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The V255I variant in the TUBB3 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V255I variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V255I variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The V255I variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus, SCV001808416.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001958980.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003305072.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. 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: 372654). This missense change has been observed in individual(s) with clinical features of TUBB3-related conditions (PMID: 34863918). 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 valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 255 of the TUBB3 protein (p.Val255Ile).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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