NM_006087.4(TUBB4A):c.763G>A (p.Val255Ile) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jun 17, 2021
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:: RCV000290772.5

Allele description [Variation Report for NM_006087.4(TUBB4A):c.763G>A (p.Val255Ile)]

NM_006087.4(TUBB4A):c.763G>A (p.Val255Ile)

Gene:

TUBB4A:tubulin beta 4A class IVa [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.3

Genomic location:

Preferred name:

NM_006087.4(TUBB4A):c.763G>A (p.Val255Ile)

HGVS:

NC_000019.10:g.6495736C>T
NG_033896.1:g.12113G>A
NM_001289123.2:c.916G>A
NM_001289127.2:c.898G>A
NM_001289129.2:c.763G>A
NM_001289130.2:c.547G>A
NM_001289131.2:c.547G>A
NM_006087.4:c.763G>AMANE SELECT
NP_001276052.1:p.Val306Ile
NP_001276056.1:p.Val300Ile
NP_001276058.1:p.Val255Ile
NP_001276059.1:p.Val183Ile
NP_001276060.1:p.Val183Ile
NP_006078.2:p.Val255Ile
NC_000019.9:g.6495747C>T
NM_001289123.1:c.916G>A
NM_006087.2:c.763G>A
NM_006087.3:c.763G>A
NP_006078.2:p.V255I

Protein change:

V183I

Links:

dbSNP: rs767399782

NCBI 1000 Genomes Browser:

rs767399782

Molecular consequence:

NM_001289123.2:c.916G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001289127.2:c.898G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001289129.2:c.763G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001289130.2:c.547G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001289131.2:c.547G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_006087.4:c.763G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000329904	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (May 18, 2021)	germline	clinical testing	Citation Link,
SCV001761992	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 17, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000329904

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(May 18, 2021)

germline

clinical testing

Citation Link,

SCV001761992

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 17, 2021)

germline

clinical testing

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

Help

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	1	not provided	clinical 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 GeneDx, SCV000329904.6

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

Description

Published functional studies demonstrate a damaging effect with significant reduction in tubulin polymerization and altered ability to incorporate into microtubules, suggestive of a toxic dominant gain-of-function mechanism (Curiel et al, 2017); Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 26934450, 25326637, 25085639, 27809427, 28973395, 32581362, 30542205)

#	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 Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001761992.1

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

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

Last Updated: Sep 29, 2024

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