NM_006087.4(TUBB4A):c.763G>A (p.Val255Ile) AND Inborn genetic diseases

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 4, 2021
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:: RCV002515471.2

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)

Name:: Inborn genetic diseases
Identifiers:: MeSH: D030342; MedGen: C0950123

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003564336	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Jun 4, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25085639, 25326637, 28973395 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003564336

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Jun 4, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

TUBB4A de novo mutations cause isolated hypomyelination.

Pizzino A, Pierson TM, Guo Y, Helman G, Fortini S, Guerrero K, Saitta S, Murphy JL, Padiath Q, Xie Y, Hakonarson H, Xu X, Funari T, Fox M, Taft RJ, van der Knaap MS, Bernard G, Schiffmann R, Simons C, Vanderver A.

Neurology. 2014 Sep 2;83(10):898-902. doi: 10.1212/WNL.0000000000000754. Epub 2014 Aug 1.

PubMed [citation]

PMID:: 25085639
PMCID:: PMC4153852

Clinical exome sequencing for genetic identification of rare Mendelian disorders.

Lee H, Deignan JL, Dorrani N, Strom SP, Kantarci S, Quintero-Rivera F, Das K, Toy T, Harry B, Yourshaw M, Fox M, Fogel BL, Martinez-Agosto JA, Wong DA, Chang VY, Shieh PB, Palmer CG, Dipple KM, Grody WW, Vilain E, Nelson SF.

JAMA. 2014 Nov 12;312(18):1880-7. doi: 10.1001/jama.2014.14604.

PubMed [citation]

PMID:: 25326637
PMCID:: PMC4278636

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV003564336.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The c.763G>A (p.V255I) alteration is located in exon 4 (coding exon 4) of the TUBB4A gene. This alteration results from a G to A substitution at nucleotide position 763, causing the valine (V) at amino acid position 255 to be replaced by an isoleucine (I). Based on data from the Genome Aggregation Database (gnomAD), the TUBB4A c.763G>A alteration was not observed, with coverage at this position. This alteration was reported de novo in a 5 year old girl with spastic quadriparesis, hypotonia, ataxia, developmental delay, and a brain MRI showing hypomyelination and mild cerebellar vermis atrophy (Pizzino, 2014). This alteration was reported de novo in another patient with developmental delay, microcephaly, truncal hypotonia, limb hypertonia, foot clonus, and cerebellar hypoplasia/atrophy (Lee, 2014). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Histo-pathological examination of brain tissue from affected individuals with the p.V255I alteration showed abnormal morphology of oligodendrocytes, and in vitro functional studies showed decreased tubulin polymerization and decreased myelin protein expression (Curiel, 2017). The p.V255I alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

#	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: Sep 29, 2024

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