A variant that is classified as pathogenic has been identified in the TUBA1A gene in a born individual of male sex. The c.518C>T, p.(Pro173Leu) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Hebebrand et al. Orphanet J. Rare. Dis., 2019 PMID: 30744660. HPO-standardized clinical features were: Hypoplasia of the corpus callosum (HP:0002079); Cerebellar vermis hypoplasia (HP:0001320); Hypoplastic hippocampus (HP:0025517); Dilation of lateral ventricles (HP:0006956); Microcephaly (HP:0000252); Spasticity, muscular hypotonia (HP:0001257, HP:0001252); Focal seizures (HP:0007359); Strabismus (HP:0000486)
ClinVar Genomic variation as it relates to human health
NM_006009.4(TUBA1A):c.518C>T (p.Pro173Leu)
Germline
Classification
Help
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.
(9)
Help
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.
Conflicting classifications of pathogenicity
Pathogenic(5); Likely pathogenic(1); Uncertain significance(1)
Pathogenic(5); Likely pathogenic(1); Uncertain significance(1)
9
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_006009.4(TUBA1A):c.518C>T (p.Pro173Leu)
Variation ID: 625511 Accession: VCV000625511.13
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12q13.12 12: 49185848 (GRCh38) [ NCBI UCSC ] 12: 49579631 (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 Apr 22, 2019 May 1, 2024 Sep 27, 2022 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_006009.4:c.518C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006000.2:p.Pro173Leu missense NM_001270399.1:c.518C>T NM_001270399.2:c.518C>T NP_001257328.1:p.Pro173Leu missense NM_001270400.2:c.413C>T NP_001257329.1:p.Pro138Leu missense NM_006009.2:c.518C>T NC_000012.12:g.49185848G>A NC_000012.11:g.49579631G>A NG_008966.1:g.8231C>T - Protein change
- P173L, P138L
- Other names
- -
- Canonical SPDI
- NC_000012.12:49185847:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
dominant_negative_variant; Sequence Ontology [ SO:0002052]
-
Global minor allele
frequency (GMAF) HelpThe 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
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| TUBA1A | No evidence available | No evidence available |
GRCh38 GRCh37 |
371 | 382 | |
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. |
|---|---|---|---|---|
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 1, 2018 | RCV000767490.2 | |
| Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Sep 27, 2022 | RCV001528974.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 1, 2021 | RCV001803973.1 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 23, 2022 | RCV002290011.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 9, 2021 | RCV002536596.2 |
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
(Jul 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Tubulinopathies
Affected status: yes
Allele origin:
de novo
|
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
Accession: SCV000898105.1
First in ClinVar: Apr 22, 2019 Last updated: Apr 22, 2019 |
Comment:
A variant that is classified as pathogenic has been identified in the TUBA1A gene in a born individual of male sex. The c.518C>T, p.(Pro173Leu) variant … (more)
A variant that is classified as pathogenic has been identified in the TUBA1A gene in a born individual of male sex. The c.518C>T, p.(Pro173Leu) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Hebebrand et al. Orphanet J. Rare. Dis., 2019 PMID: 30744660. HPO-standardized clinical features were: Hypoplasia of the corpus callosum (HP:0002079); Cerebellar vermis hypoplasia (HP:0001320); Hypoplastic hippocampus (HP:0025517); Dilation of lateral ventricles (HP:0006956); Microcephaly (HP:0000252); Spasticity, muscular hypotonia (HP:0001257, HP:0001252); Focal seizures (HP:0007359); Strabismus (HP:0000486) (less)
Number of individuals with the variant: 2
Sex: male
Ethnicity/Population group: German
|
|
|
Pathogenic
(Nov 01, 2021)
|
criteria provided, single submitter
Method: research
|
Tubulinopathy-associated dysgyria
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg
Accession: SCV002047679.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Clinical Features:
Microcephaly (present) , Global developmental delay (present) , Infantile muscular hypotonia (present) , Poor gross motor coordination (present) , Congenital bilateral perisylvian syndrome (present)
Segregation observed: no
Secondary finding: no
|
|
|
Pathogenic
(Mar 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Lissencephaly due to TUBA1A mutation
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002580279.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS2_VSTR, PM2_SUP, PP2, PP3
|
Number of individuals with the variant: 1
Sex: female
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Lissencephaly due to TUBA1A mutation
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002820204.1
First in ClinVar: Jan 21, 2023 Last updated: Jan 21, 2023 |
Comment:
The missense variant p.P173L in TUBA1A (NM_006009.4) has been previously reported in an individual affected with TUBA1A-associated tubulinopathy (Hebebrand et al, 2019). The p.P173L variant … (more)
The missense variant p.P173L in TUBA1A (NM_006009.4) has been previously reported in an individual affected with TUBA1A-associated tubulinopathy (Hebebrand et al, 2019). The p.P173L variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between proline and leucine. The p.P173L missense variant is predicted to be damaging by both SIFT and PolyPhen2. The proline residue at codon 173 of TUBA1A is conserved in all mammalian species. The nucleotide c.518 in TUBA1A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. (less)
Clinical Features:
Global developmental delay (present) , Cafe-au-lait spot (present) , Microcephaly (present) , Ankyloglossia (present)
|
|
|
Pathogenic
(Mar 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002499022.2
First in ClinVar: Apr 16, 2022 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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: 28714951, 25363768, 22495306, 28407358, 30744660, 34011629, 33726816, 31785789, 35017693, 24860126) (less)
|
|
|
Uncertain significance
(Sep 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003441259.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this … (more)
This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: 625511). This missense change has been observed in individual(s) with tubulinopathy (PMID: 24860126). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 173 of the TUBA1A protein (p.Pro173Leu). (less)
|
|
|
Pathogenic
(Nov 09, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003706329.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.518C>T (p.P173L) alteration is located in exon 4 (coding exon 4) of the TUBA1A gene. This alteration results from a C to T substitution … (more)
The c.518C>T (p.P173L) alteration is located in exon 4 (coding exon 4) of the TUBA1A gene. This alteration results from a C to T substitution at nucleotide position 518, causing the proline (P) at amino acid position 173 to be replaced by a leucine (L). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported de novo in multiple unrelated patients with global developmental delay, cortical and subcortical malformations, microcephaly, spasticity, and epilepsy (Bahi-Buisson, 2014; Hebebrand, 2019; DECIPHER). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001797905.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001741646.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
Comment:
Comment:
The missense variant p.P173L in TUBA1A (NM_006009.4) has been previously reported in an individual affected with TUBA1A-associated tubulinopathy (Hebebrand et al, 2019). The p.P173L variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between proline and leucine. The p.P173L missense variant is predicted to be damaging by both SIFT and PolyPhen2. The proline residue at codon 173 of TUBA1A is conserved in all mammalian species. The nucleotide c.518 in TUBA1A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Comment:
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: 28714951, 25363768, 22495306, 28407358, 30744660, 34011629, 33726816, 31785789, 35017693, 24860126)
Comment:
This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: 625511). This missense change has been observed in individual(s) with tubulinopathy (PMID: 24860126). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 173 of the TUBA1A protein (p.Pro173Leu).
Comment:
The c.518C>T (p.P173L) alteration is located in exon 4 (coding exon 4) of the TUBA1A gene. This alteration results from a C to T substitution at nucleotide position 518, causing the proline (P) at amino acid position 173 to be replaced by a leucine (L). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported de novo in multiple unrelated patients with global developmental delay, cortical and subcortical malformations, microcephaly, spasticity, and epilepsy (Bahi-Buisson, 2014; Hebebrand, 2019; DECIPHER). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
dominant_negative_variant
|
|
|
Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg
Accession: SCV002047679.1
|
|
Comment:
A variant that is classified as pathogenic has been identified in the TUBA1A gene in a born individual of male sex. The c.518C>T, p.(Pro173Leu) variant has been reported as a variant of de novo origin. This variant and associated phenotype was previously reported by Hebebrand et al. Orphanet J. Rare. Dis., 2019 PMID: 30744660. HPO-standardized clinical features were: Hypoplasia of the corpus callosum (HP:0002079); Cerebellar vermis hypoplasia (HP:0001320); Hypoplastic hippocampus (HP:0025517); Dilation of lateral ventricles (HP:0006956); Microcephaly (HP:0000252); Spasticity, muscular hypotonia (HP:0001257, HP:0001252); Focal seizures (HP:0007359); Strabismus (HP:0000486)
Comment:
The missense variant p.P173L in TUBA1A (NM_006009.4) has been previously reported in an individual affected with TUBA1A-associated tubulinopathy (Hebebrand et al, 2019). The p.P173L variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between proline and leucine. The p.P173L missense variant is predicted to be damaging by both SIFT and PolyPhen2. The proline residue at codon 173 of TUBA1A is conserved in all mammalian species. The nucleotide c.518 in TUBA1A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Comment:
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: 28714951, 25363768, 22495306, 28407358, 30744660, 34011629, 33726816, 31785789, 35017693, 24860126)
Comment:
This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: 625511). This missense change has been observed in individual(s) with tubulinopathy (PMID: 24860126). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 173 of the TUBA1A protein (p.Pro173Leu).
Comment:
The c.518C>T (p.P173L) alteration is located in exon 4 (coding exon 4) of the TUBA1A gene. This alteration results from a C to T substitution at nucleotide position 518, causing the proline (P) at amino acid position 173 to be replaced by a leucine (L). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported de novo in multiple unrelated patients with global developmental delay, cortical and subcortical malformations, microcephaly, spasticity, and epilepsy (Bahi-Buisson, 2014; Hebebrand, 2019; DECIPHER). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The mutational and phenotypic spectrum of TUBA1A-associated tubulinopathy. | Hebebrand M | Orphanet journal of rare diseases | 2019 | PMID: 30744660 |
| Vitamin D-related genes are subjected to significant de novo mutation burdens in autism spectrum disorder. | Li J | American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics | 2017 | PMID: 28407358 |
| The contribution of de novo coding mutations to autism spectrum disorder. | Iossifov I | Nature | 2014 | PMID: 25363768 |
| The wide spectrum of tubulinopathies: what are the key features for the diagnosis? | Bahi-Buisson N | Brain : a journal of neurology | 2014 | PMID: 24860126 |
| De novo mutations revealed by whole-exome sequencing are strongly associated with autism. | Sanders SJ | Nature | 2012 | PMID: 22495306 |
Text-mined citations for rs1565627304 ...
HelpThese 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 Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.