NM_006009.4(TUBA1A):c.449C>T (p.Thr150Ile) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 30, 2021
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:: RCV001550367.9

Allele description [Variation Report for NM_006009.4(TUBA1A):c.449C>T (p.Thr150Ile)]

NM_006009.4(TUBA1A):c.449C>T (p.Thr150Ile)

Gene:

TUBA1A:tubulin alpha 1a [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q13.12

Genomic location:

Preferred name:

NM_006009.4(TUBA1A):c.449C>T (p.Thr150Ile)

HGVS:

NC_000012.12:g.49185917G>A
NG_008966.1:g.8162C>T
NM_001270399.2:c.449C>T
NM_001270400.2:c.344C>T
NM_006009.4:c.449C>TMANE SELECT
NP_001257328.1:p.Thr150Ile
NP_001257329.1:p.Thr115Ile
NP_006000.2:p.Thr150Ile
NC_000012.11:g.49579700G>A
NM_006009.2:c.449C>T
NM_006009.3:c.449C>T

Protein change:

T115I

Links:

dbSNP: rs1565627339

NCBI 1000 Genomes Browser:

rs1565627339

Molecular consequence:

NM_001270399.2:c.449C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001270400.2:c.344C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_006009.4:c.449C>T - 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
SCV001770682	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jun 29, 2019)	germline	clinical testing	Citation Link,
SCV002222004	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 30, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28677066, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001770682

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jun 29, 2019)

germline

clinical testing

Citation Link,

SCV002222004

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 30, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

Citations

PubMed

Romaniello R, Arrigoni F, Panzeri E, Poretti A, Micalizzi A, Citterio A, Bedeschi MF, Berardinelli A, Cusmai R, D'Arrigo S, Ferraris A, Hackenberg A, Kuechler A, Mancardi M, Nuovo S, Oehl-Jaschkowitz B, Rossi A, Signorini S, Tüttelmann F, Wahl D, Hehr U, Boltshauser E, et al.

Eur Radiol. 2017 Dec;27(12):5080-5092. doi: 10.1007/s00330-017-4945-2. Epub 2017 Jul 4. Erratum in: Eur Radiol. 2017 Dec;27(12):5093. doi: 10.1007/s00330-017-4986-6.

PubMed [citation]

PMID:: 28677066

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, SCV001770682.1

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

Description

Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30744660, 28677066)

#	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, SCV002222004.3

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

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with clinical features of tubulin-related cortical malformations (PMID: 28677066). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 625509). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 150 of the TUBA1A protein (p.Thr150Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine.

#	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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