VCV000127191.8 - ClinVar

NM_178014.4(TUBB):c.1201G>A (p.Glu401Lys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(6)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_178014.4(TUBB):c.1201G>A (p.Glu401Lys)

Variation ID: 127191 Accession: VCV000127191.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p21.33 6: 30724263 (GRCh38) [ NCBI UCSC ] 6: 30692040 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jan 8, 2018	Nov 3, 2024	Apr 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_178014.4:c.1201G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_821133.1:p.Glu401Lys	missense
NM_001293212.2:c.1261G>A	NP_001280141.1:p.Glu421Lys	missense
NM_001293213.2:c.595G>A	NP_001280142.1:p.Glu199Lys	missense
NM_001293214.2:c.1069G>A	NP_001280143.1:p.Glu357Lys	missense
NM_001293215.2:c.985G>A	NP_001280144.1:p.Glu329Lys	missense
NM_001293216.2:c.985G>A	NP_001280145.1:p.Glu329Lys	missense
NM_178014.3:c.1201G>A
NR_120608.2:n.757G>A		non-coding transcript variant
NC_000006.12:g.30724263G>A
NC_000006.11:g.30692040G>A
NG_034142.1:g.9063G>A
	P07437:p.Glu401Lys

... more HGVS ... less HGVS

Protein change

E401K, E357K, E329K, E421K, E199K

Other names

Canonical SPDI

NC_000006.12:30724262:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA151417 UniProtKB: P07437#VAR_071765 OMIM: 191130.0003 dbSNP: rs587777357 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TUBB		-	-	GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh38 GRCh37	99	106

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Complex cortical dysplasia with other brain malformations 6	Pathogenic (2)	criteria provided, single submitter	Jun 15, 2023	RCV000115020.7
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Jan 20, 2016	RCV000624500.2
Multiple benign circumferential skin creases on limbs 1	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 23, 2023	RCV002274914.3
not provided	Pathogenic (1)	criteria provided, single submitter	Apr 23, 2024	RCV004772839.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Apr 23, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005385556.1 First in ClinVar: Nov 03, 2024 Last updated: Nov 03, 2024	Comment: Published functional studies demonstrate a damaging effect (PMID: 23246003, 24833723); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that … (more) Published functional studies demonstrate a damaging effect (PMID: 23246003, 24833723); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23246003, 24833723, 35183220, 30738969) (less)
Pathogenic (Aug 16, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Multiple benign circumferential skin creases on limbs 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV002562206.1 First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022	Clinical Features: Microcephaly (present) , Progressive microcephaly (present) , Retrognathia (present) , Macrotia (present) , Abnormal thorax morphology (present) , Hypopigmentation of the skin (present) , Fragile … (more) Microcephaly (present) , Progressive microcephaly (present) , Retrognathia (present) , Macrotia (present) , Abnormal thorax morphology (present) , Hypopigmentation of the skin (present) , Fragile skin (present) , Large hands (present) , Global developmental delay (present) , Failure to thrive (present) , Generalized hypopigmentation (present) , Asymmetrical gluteal crease (present) (less)
Pathogenic (Feb 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Multiple benign circumferential skin creases on limbs 1 Affected status: yes Allele origin: unknown	3billion Accession: SCV003841998.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Publications: PubMed (1) PubMed: 23246003 Comment: 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 … (more) 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: 0.77; 3Cnet: 0.93). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000127191). The variant has been previously reported as de novo in a similarly affected individual (PMID: 23246003). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Abnormal heart morphology (present) , Mild microcephaly (present) , Macrotia (present) , Depressed nasal bridge (present) , Long philtrum (present) , Abnormality of the dentition … (more) Abnormal heart morphology (present) , Mild microcephaly (present) , Macrotia (present) , Depressed nasal bridge (present) , Long philtrum (present) , Abnormality of the dentition (present) (less)
Pathogenic (Jan 20, 2016)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV000741265.3 First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023	Number of individuals with the variant: 1 Clinical Features: Hypertensive disorder (present) , Pheochromocytoma (present) , Microcephaly (present) , Short stature (present) , Scoliosis (present) , Aortic root dilatation (present) , Cryptorchidism (present) , … (more) Hypertensive disorder (present) , Pheochromocytoma (present) , Microcephaly (present) , Short stature (present) , Scoliosis (present) , Aortic root dilatation (present) , Cryptorchidism (present) , Hernia (present) , Joint hypermobility (present) , Pes planus (present) , Patellar dislocation (present) , Deeply set eye (present) , Prominent supraorbital ridges (present) , Prominent nasal bridge (present) , Bulbous nose (present) , Webbed neck (present) , Cutis marmorata (present) , Short foot (present) , Broad toe (present) , Muscular hypotonia (present) , Neurodevelopmental delay (present) , Autistic behavior (present) , Hearing impairment (present) , Blurred vision (present) , Headache (present) , Nausea (present) (less) Sex: male Ethnicity/Population group: Caucasian/Ashkenazi Jewish
Pathogenic (Jun 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Complex cortical dysplasia with other brain malformations 6 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004175194.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Publications: PubMed (4) PubMed: 23246003‚ 24833723‚ 30738969‚ 35183200 Comment: The TUBB c.1201G>A variant is classified as a PATHOGENIC variant (PS2, PS3, PS4_moderate, PM2, PP3). The TUBB c.1201G>A variant is a single nucleotide change in … (more) The TUBB c.1201G>A variant is classified as a PATHOGENIC variant (PS2, PS3, PS4_moderate, PM2, PP3). The TUBB c.1201G>A variant is a single nucleotide change in exon 4/4 of the TUBB gene, which is predicted to change the amino acid glutamic acid at position 401 in the protein to lysine. The variant is in dbSNP (rs587777357) but is absent from population databases (PM2). Additionally, the variant has been previously detected in multiple unrelated individuals with clinical features of microcephaly and neurodevelopmental disease (PMID: 23246003, 30738969, 35183200) (PS4_moderate). Functional studies have demonstrated that this variant disrupted the morphology of cortical neurons, resulting in defects in synaptic signaling and the polymerization rates of the microtuble cytoskeleton (PMID: 23246003, 24833723) (PS3). The patient is de novo for this variant (PS2). The variant has been reported in ClinVar (Variation ID: 127191) or HGMD (Accession no.: CM1212023) as Pathogenic/ disease causing. Computational prediction support a deleterious effect on the gene or gene product (PP3). Clinical review is recommended. (less)
Pathogenic (Dec 27, 2012)	no assertion criteria provided Method: literature only	CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 6 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000148929.4 First in ClinVar: May 05, 2014 Last updated: Sep 23, 2023	Publications: Breuss, M., Heng, J. I.-T., (more...) Breuss, M., Heng, J. I.-T., Poirier, K., Tian, G., Jaglin, X. H., Qu, Z., Braun, A., Gstrein, T., Ngo, L., Haas, M., Bahi-Buisson, N., Moutard, M. L., and 11 others Mutations in the beta-tubulin gene TUBB5 cause microcephaly with structural brain abnormalities. Cell Rep. 2: 1554-1562, 2012. Comment on evidence: In a 2-year-old girl of Vietnamese and Caucasian descent with complex cortical dysplasia with other brain malformations-6 (CDCBM6; 615771), Breuss et al. (2012) identified a … (more) In a 2-year-old girl of Vietnamese and Caucasian descent with complex cortical dysplasia with other brain malformations-6 (CDCBM6; 615771), Breuss et al. (2012) identified a de novo heterozygous mutation in the TUBB gene, resulting in a glu401-to-lys (E401K) substitution at a highly conserved residue on the surface of the intradimer interface. In vitro functional expression assays showed that the E401K mutation arrested the assembly pathway of alpha/beta-tubulin; the mutant protein was unable to coassemble into a tubulin heterodimer but was instead distributed throughout the cytoplasm. Overexpression of the mutant protein in the developing mouse brain resulted in a mild increase in the mitotic index of neurons and decreased the number of neurons in the cortical plate, similar to findings observed in Tubb-null mice. The findings were consistent with a neuronal migratory defect. The patient had mild developmental delay, microcephaly (-4 SD), dysmorphic basal ganglia, and partial agenesis of the corpus callosum. Cortical dysgenesis was not apparent. (less)

Comment:

Published functional studies demonstrate a damaging effect (PMID: 23246003, 24833723); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23246003, 24833723, 35183220, 30738969)

Comment:

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: 0.77; 3Cnet: 0.93). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000127191). The variant has been previously reported as de novo in a similarly affected individual (PMID: 23246003). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

The TUBB c.1201G>A variant is classified as a PATHOGENIC variant (PS2, PS3, PS4_moderate, PM2, PP3). The TUBB c.1201G>A variant is a single nucleotide change in exon 4/4 of the TUBB gene, which is predicted to change the amino acid glutamic acid at position 401 in the protein to lysine. The variant is in dbSNP (rs587777357) but is absent from population databases (PM2). Additionally, the variant has been previously detected in multiple unrelated individuals with clinical features of microcephaly and neurodevelopmental disease (PMID: 23246003, 30738969, 35183200) (PS4_moderate). Functional studies have demonstrated that this variant disrupted the morphology of cortical neurons, resulting in defects in synaptic signaling and the polymerization rates of the microtuble cytoskeleton (PMID: 23246003, 24833723) (PS3). The patient is de novo for this variant (PS2). The variant has been reported in ClinVar (Variation ID: 127191) or HGMD (Accession no.: CM1212023) as Pathogenic/ disease causing. Computational prediction support a deleterious effect on the gene or gene product (PP3). Clinical review is recommended.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Cucurbitacin B inhibits TGF-β1-induced epithelial-mesenchymal transition (EMT) in NSCLC through regulating ROS and PI3K/Akt/mTOR pathways.	Yuan R	Chinese medicine	2022	PMID: 35183200
Spectrum of clinical heterogeneity of β-tubulin TUBB5 gene mutations.	Madrigal I	Gene	2019	PMID: 30738969
TUBB5 and its disease-associated mutations influence the terminal differentiation and dendritic spine densities of cerebral cortical neurons.	Ngo L	Human molecular genetics	2014	PMID: 24833723
Mutations in the β-tubulin gene TUBB5 cause microcephaly with structural brain abnormalities.	Breuss M	Cell reports	2012	PMID: 23246003

Text-mined citations for rs587777357 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_178014.4(TUBB):c.1201G>A (p.Glu401Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587777357 ...