NM_006009.4(TUBA1A):c.641G>A (p.Arg214His) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Dec 27, 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:: RCV000413283.27

Allele description [Variation Report for NM_006009.4(TUBA1A):c.641G>A (p.Arg214His)]

NM_006009.4(TUBA1A):c.641G>A (p.Arg214His)

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.641G>A (p.Arg214His)

HGVS:

NC_000012.12:g.49185725C>T
NG_008966.1:g.8354G>A
NM_001270399.2:c.641G>A
NM_001270400.2:c.536G>A
NM_006009.4:c.641G>AMANE SELECT
NP_001257328.1:p.Arg214His
NP_001257328.1:p.Arg214His
NP_001257329.1:p.Arg179His
NP_006000.2:p.Arg214His
NC_000012.11:g.49579508C>T
NM_001270399.1:c.641G>A
NM_006009.2:c.641G>A
NM_006009.3:c.641G>A
p.Arg214His

Protein change:

R179H

Links:

dbSNP: rs1057517843

NCBI 1000 Genomes Browser:

rs1057517843

Molecular consequence:

NM_001270399.2:c.641G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001270400.2:c.536G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_006009.4:c.641G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000490865	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 13, 2020)	germline	clinical testing	Citation Link,
SCV000511367	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 3, 2017)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001247150	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Dec 1, 2018)	germline	clinical testing	Citation Link,
SCV001581353	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 27, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 24860126, 26130693, 29158550, 28492532

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
not provided	de novo	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	2	not provided	not provided	not provided	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

The wide spectrum of tubulinopathies: what are the key features for the diagnosis?

Bahi-Buisson N, Poirier K, Fourniol F, Saillour Y, Valence S, Lebrun N, Hully M, Bianco CF, Boddaert N, Elie C, Lascelles K, Souville I; LIS-Tubulinopathies Consortium., Beldjord C, Chelly J.

Brain. 2014 Jun;137(Pt 6):1676-700. doi: 10.1093/brain/awu082.

PubMed [citation]

PMID:: 24860126

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000490865.3

#	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); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32570172, 30087272, 30744660, 28677066, 26934450, 24860126, 25059107, 26130693, 29158550)

#	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 Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, SCV000511367.1

#	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	de novo	not provided	not provided	not provided	not provided		not provided	0.000082	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001247150.20

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

#	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		2	not provided	not provided	not provided

From Invitae, SCV001581353.4

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

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TUBA1A function (PMID: 26130693). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). ClinVar contains an entry for this variant (Variation ID: 372542). This missense change has been observed in individual(s) with lissencephaly, including several cases in which the variant was observed to be de novo (PMID: 24860126, 26130693, 29158550; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 214 of the TUBA1A protein (p.Arg214His).

#	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: Apr 15, 2024

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