NM_006087.4(TUBB4A):c.763G>A (p.Val255Ile) AND Hypomyelinating leukodystrophy 6

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Mar 26, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000199587.13

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:: Hypomyelinating leukodystrophy 6
Synonyms:: LEUKODYSTROPHY, HYPOMYELINATING, WITH ATROPHY OF THE BASAL GANGLIA AND CEREBELLUM; TUBB4A-Associated Leukodystrophy
Identifiers:: MONDO: MONDO:0012905; MedGen: C2676244; Orphanet: 139441; OMIM: 612438

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LOC125657098 [Ostrea edulis]
LOC125657098 [Ostrea edulis]
Gene ID:125657098

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000255501	UCLA Clinical Genomics Center, UCLA - CES	criteria provided, single submitter (Lee et al. (JAMA. 2014))	Likely pathogenic (Apr 2, 2013)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000328466	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000586833	TIDEX, University of British Columbia	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	de novo	research	PubMed (1) [See all records that cite this PMID]
SCV000828297	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 4, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25085639, 25326637, 28973395, 28492532
SCV004807039	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 26, 2024)	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	de novo	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Asian	de novo	yes	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 (5)

Details of each submission

From UCLA Clinical Genomics Center, UCLA - CES, SCV000255501.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Asian	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	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV000328466.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

#	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 TIDEX, University of British Columbia, SCV000586833.1

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

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000828297.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 255 of the TUBB4A protein (p.Val255Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dystonia, isolated hypomyelination, or dystonia with hypomyelinating leukodystrophy (PMID: 25085639, 25326637; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 217025). 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 TUBB4A protein function. Experimental studies have shown that this missense change affects TUBB4A function (PMID: 28973395). For these reasons, this variant has been classified as 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

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004807039.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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