NM_006087.4(TUBB4A):c.1078G>C (p.Gly360Arg) AND Hypomyelinating leukodystrophy 6

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 22, 2023
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:: RCV003741984.1

Allele description

NM_006087.4(TUBB4A):c.1078G>C (p.Gly360Arg)

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.1078G>C (p.Gly360Arg)

HGVS:

NC_000019.10:g.6495421C>G
NG_033896.1:g.12428G>C
NM_001289123.2:c.1231G>C
NM_001289127.2:c.1213G>C
NM_001289129.2:c.1078G>C
NM_001289130.2:c.862G>C
NM_001289131.2:c.862G>C
NM_006087.4:c.1078G>CMANE SELECT
NP_001276052.1:p.Gly411Arg
NP_001276056.1:p.Gly405Arg
NP_001276058.1:p.Gly360Arg
NP_001276059.1:p.Gly288Arg
NP_001276060.1:p.Gly288Arg
NP_006078.2:p.Gly360Arg
NC_000019.9:g.6495432C>G

Protein change:

G288R

Molecular consequence:

NM_001289123.2:c.1231G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001289127.2:c.1213G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001289129.2:c.1078G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001289130.2:c.862G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001289131.2:c.862G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_006087.4:c.1078G>C - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004435268	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 22, 2023)	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

SCV004435268

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 22, 2023)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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 Invitae, SCV004435268.1

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

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 360 of the TUBB4A protein (p.Gly360Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TUBB4A-related conditions. 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.

#	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: Feb 28, 2024

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