NM_006009.4(TUBA1A):c.641G>A (p.Arg214His) AND Lissencephaly due to TUBA1A mutation

Germline classification:: Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:: Nov 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:: RCV000496159.13

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)

Name:: Lissencephaly due to TUBA1A mutation (LIS3)
Synonyms:: Lissencephaly 3
Identifiers:: MONDO: MONDO:0012703; MedGen: C4305153; Orphanet: 171680; OMIM: 611603

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dyskerin, partial [Phascolion strombus]
dyskerin, partial [Phascolion strombus]
gi|119874643|gb|ABM05798.1|

Protein
ADE16 bifunctional phosphoribosylaminoimidazolecarboxamide formyltransferase/IMP...
ADE16 bifunctional phosphoribosylaminoimidazolecarboxamide formyltransferase/IMP cyclohydrolase ADE16 [Saccharomyces cerevisiae S288C]
Gene ID:850715

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000586724	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 1, 2017)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000893302	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001164438	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 3, 2018)	de novo	research	PubMed (1) [See all records that cite this PMID]
SCV001368118	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 1, 2016)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001526062	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 2, 2018)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002521449	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 22, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003807814	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 25, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004102652	Daryl Scott Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 10, 2023)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	2	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, research

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

PMC

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.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, SCV000586724.1

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

Description

De novo missense variant identified in a female patient with severe ID, severe epilepsy, developmental regression, scoliosis, hypotonia, MRI: agenesis of corpus callosum, Dandy-Walker malformation, opticus hypoplasia, delayed bone age.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV000893302.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001164438.1

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

Description

The heterozygous p.Arg214His variant in TUBA1A was identified by our study in one individual with lissencephaly. Trio exome analysis showed this variant to be de novo. This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The TUBA1A gene has a low rate of benign missense variation, supporting that a change in this position may not be tolerated. This variant has been reported in ClinVar (Variation ID: 372542). Multiple reports of de novo inheritance of this variant were reported in ClinVar and the literature. In summary, the p.Arg214His variant is pathogenic based off of our findings, multiple de novo reports in ClinVar, and the literature. ACMG/AMP Criteria applied: PM2, PS2, PM6_Strong, PP2 (Richards 2015).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001368118.2

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

Description

This variant was classified as: Likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001526062.1

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

Description

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002521449.1

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

Description

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.79; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000372542). Different missense changes at the same codon (p.Arg214Cys, p.Arg214Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000432708, VCV001187068). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV003807814.1

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

Description

ACMG classification criteria: PS4 strong, PM2 moderated, PM6 moderated, PP2 supporting, PP3 supporting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Daryl Scott Lab, Baylor College of Medicine, SCV004102652.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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