VCV000864866.26 - ClinVar

NM_006009.4(TUBA1A):c.958C>T (p.Arg320Cys)

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/Likely 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_006009.4(TUBA1A):c.958C>T (p.Arg320Cys)

Variation ID: 864866 Accession: VCV000864866.26

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q13.12 12: 49185408 (GRCh38) [ NCBI UCSC ] 12: 49579191 (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 18, 2020	Oct 20, 2024	Feb 27, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_006009.4:c.958C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006000.2:p.Arg320Cys	missense
NM_001270399.2:c.958C>T	NP_001257328.1:p.Arg320Cys	missense
NM_001270400.2:c.853C>T	NP_001257329.1:p.Arg285Cys	missense
NM_006009.2:c.958C>T
NM_006009.3:c.958C>T
NC_000012.12:g.49185408G>A
NC_000012.11:g.49579191G>A
NG_008966.1:g.8671C>T

... more HGVS ... less HGVS

Protein change

R285C, R320C

Other names

Canonical SPDI

NC_000012.12:49185407: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

dbSNP: rs1942168488 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.
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.
Lissencephaly due to TUBA1A mutation	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Feb 2, 2022	RCV001072149.8
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 27, 2023	RCV002067728.18

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 (Jan 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Lissencephaly due to TUBA1A mutation (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Bruce Lefroy Centre, Murdoch Childrens Research Institute Accession: SCV001235715.2 First in ClinVar: Apr 18, 2020 Last updated: May 04, 2020	Comment: PS1, PM2, PM6, PP2, PP3
Likely pathogenic (Nov 30, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lissencephaly due to TUBA1A mutation Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002811042.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Feb 27, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002496253.3 First in ClinVar: Apr 08, 2022 Last updated: Mar 11, 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: 24860126, 33604570, 34958143) (less)
Pathogenic (Feb 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lissencephaly due to TUBA1A mutation (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002557774.2 First in ClinVar: Aug 08, 2022 Last updated: Jul 23, 2024	Publications: PubMed (4) PubMed: 20466733‚ 30517687‚ 30744660‚ 33604570 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Both loss of functional and dominant negative are suspected mechanisms (PMIDs: 20466733, 30517687). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Arg320His) has been reported in at least two patients diagnosed with microlissencephaly, including a report of a de novo event. It has also been classified as likely pathogenic by a diagnostic laboratory in ClinVar (PMID: 30744660). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been identified in at least two patients with polymicrogyria and multiple brain malformations as de novo events and classified as likely pathogenic by a diagnostic laboratory in ClinVar (PMID: 33604570; VCGS internal cohort). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Nov 01, 2020)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002563121.16 First in ClinVar: Aug 23, 2022 Last updated: Oct 20, 2024	Number of individuals with the variant: 2
Likely pathogenic (May 06, 2020)	no assertion criteria provided Method: clinical testing	Lissencephaly due to TUBA1A mutation Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001469181.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021

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: 24860126, 33604570, 34958143)

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Both loss of functional and dominant negative are suspected mechanisms (PMIDs: 20466733, 30517687). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Arg320His) has been reported in at least two patients diagnosed with microlissencephaly, including a report of a de novo event. It has also been classified as likely pathogenic by a diagnostic laboratory in ClinVar (PMID: 30744660). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been identified in at least two patients with polymicrogyria and multiple brain malformations as de novo events and classified as likely pathogenic by a diagnostic laboratory in ClinVar (PMID: 33604570; VCGS internal cohort). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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
Genetic heterogeneity of polymicrogyria: study of 123 patients using deep sequencing.	Stutterd CA	Brain communications	2020	PMID: 33604570
The mutational and phenotypic spectrum of TUBA1A-associated tubulinopathy.	Hebebrand M	Orphanet journal of rare diseases	2019	PMID: 30744660
TUBA1A mutations identified in lissencephaly patients dominantly disrupt neuronal migration and impair dynein activity.	Aiken J	Human molecular genetics	2019	PMID: 30517687
TUBA1A mutations cause wide spectrum lissencephaly (smooth brain) and suggest that multiple neuronal migration pathways converge on alpha tubulins.	Kumar RA	Human molecular genetics	2010	PMID: 20466733

Text-mined citations for rs1942168488 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_006009.4(TUBA1A):c.958C>T (p.Arg320Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1942168488 ...