NM_006009.4(TUBA1A):c.1265G>A (p.Arg422His) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jun 3, 2022
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:: RCV000255074.10

Allele description [Variation Report for NM_006009.4(TUBA1A):c.1265G>A (p.Arg422His)]

NM_006009.4(TUBA1A):c.1265G>A (p.Arg422His)

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.1265G>A (p.Arg422His)

HGVS:

NC_000012.12:g.49185101C>T
NG_008966.1:g.8978G>A
NM_001270399.2:c.1265G>A
NM_001270400.2:c.1160G>A
NM_006009.4:c.1265G>AMANE SELECT
NP_001257328.1:p.Arg422His
NP_001257329.1:p.Arg387His
NP_006000.2:p.Arg422His
NC_000012.11:g.49578884C>T
NM_006009.2:c.1265G>A
NM_006009.3:c.1265G>A

Protein change:

R387H; ARG422HIS

Links:

OMIM: 602529.0008; dbSNP: rs137853050

NCBI 1000 Genomes Browser:

rs137853050

Molecular consequence:

NM_001270399.2:c.1265G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001270400.2:c.1160G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_006009.4:c.1265G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000321986	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 23, 2021)	germline	clinical testing	Citation Link,
SCV002148511	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 3, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18728072, 20466733, 26350204, 29671837, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000321986

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Oct 23, 2021)

germline

clinical testing

Citation Link,

SCV002148511

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 3, 2022)

germline

clinical testing

PubMed (5)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Refinement of cortical dysgeneses spectrum associated with TUBA1A mutations.

Bahi-Buisson N, Poirier K, Boddaert N, Saillour Y, Castelnau L, Philip N, Buyse G, Villard L, Joriot S, Marret S, Bourgeois M, Van Esch H, Lagae L, Amiel J, Hertz-Pannier L, Roubertie A, Rivier F, Pinard JM, Beldjord C, Chelly J.

J Med Genet. 2008 Oct;45(10):647-53. doi: 10.1136/jmg.2008.058073. Epub 2008 Aug 26.

PubMed [citation]

PMID:: 18728072

TUBA1A mutations cause wide spectrum lissencephaly (smooth brain) and suggest that multiple neuronal migration pathways converge on alpha tubulins.

Kumar RA, Pilz DT, Babatz TD, Cushion TD, Harvey K, Topf M, Yates L, Robb S, Uyanik G, Mancini GM, Rees MI, Harvey RJ, Dobyns WB.

Hum Mol Genet. 2010 Jul 15;19(14):2817-27. doi: 10.1093/hmg/ddq182. Epub 2010 May 12.

PubMed [citation]

PMID:: 20466733
PMCID:: PMC2893812

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000321986.8

#	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 (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 21875651, 25059107, 24860126, 22264709, 18669490, 29671837, 20466733, 26350204, 18954413, 20376468, 22948023, 18728072, 33453472, 30744660)

#	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 Invitae, SCV002148511.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg422 amino acid residue in TUBA1A. Other variant(s) that disrupt this residue have been observed in individuals with TUBA1A-related conditions (PMID: 18728072), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 7077). This missense change has been observed in individual(s) with cortical malformations (PMID: 18728072, 20466733, 26350204, 29671837). 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 422 of the TUBA1A protein (p.Arg422His).

#	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 14, 2024

ClinVar

Relating variation to medicine