NM_006009.4(TUBA1A):c.629A>G (p.Tyr210Cys) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 10, 2023
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:: RCV001388958.7

Allele description [Variation Report for NM_006009.4(TUBA1A):c.629A>G (p.Tyr210Cys)]

NM_006009.4(TUBA1A):c.629A>G (p.Tyr210Cys)

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.629A>G (p.Tyr210Cys)

HGVS:

NC_000012.12:g.49185737T>C
NG_008966.1:g.8342A>G
NM_001270399.2:c.629A>G
NM_001270400.2:c.524A>G
NM_006009.2:c.629A>G
NM_006009.4:c.629A>GMANE SELECT
NP_001257328.1:p.Tyr210Cys
NP_001257329.1:p.Tyr175Cys
NP_006000.2:p.Tyr210Cys
NC_000012.11:g.49579520T>C
NM_006009.3:c.629A>G

Protein change:

Y175C

Links:

dbSNP: rs1565627253

NCBI 1000 Genomes Browser:

rs1565627253

Molecular consequence:

NM_001270399.2:c.629A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001270400.2:c.524A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_006009.4:c.629A>G - 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
SCV001590144	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 15, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21403111, 28492532
SCV004025495	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Aug 10, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001590144

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 15, 2022)

germline

clinical testing

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

SCV004025495

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Aug 10, 2023)

germline

clinical testing

Citation Link

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

TUBA1A mutations: from isolated lissencephaly to familial polymicrogyria.

Jansen AC, Oostra A, Desprechins B, De Vlaeminck Y, Verhelst H, Régal L, Verloo P, Bockaert N, Keymolen K, Seneca S, De Meirleir L, Lissens W.

Neurology. 2011 Mar 15;76(11):988-92. doi: 10.1212/WNL.0b013e31821043f5.

PubMed [citation]

PMID:: 21403111

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV001590144.4

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

Description

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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 TUBA1A protein function. ClinVar contains an entry for this variant (Variation ID: 625474). This missense change has been observed in individual(s) with lissencephaly (PMID: 21403111). In at least one individual the variant was observed to be de novo. This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 210 of the TUBA1A protein (p.Tyr210Cys).

#	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 GeneDx, SCV004025495.1

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); 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: 21403111, 26493046, 28412269, 22264709, 30744660, 35892608)

#	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

Last Updated: Feb 14, 2024

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