VCV000438586.5 - ClinVar

NM_178014.4(TUBB):c.860C>T (p.Pro287Leu)

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.

Conflicting classifications of pathogenicity
Pathogenic(3); Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_178014.4(TUBB):c.860C>T (p.Pro287Leu)

Variation ID: 438586 Accession: VCV000438586.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p21.33 6: 30723922 (GRCh38) [ NCBI UCSC ] 6: 30691699 (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	Jun 2, 2018	May 19, 2024	Nov 23, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_178014.4:c.860C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_821133.1:p.Pro287Leu	missense
NM_001293212.2:c.920C>T	NP_001280141.1:p.Pro307Leu	missense
NM_001293213.2:c.370-116C>T		intron variant
NM_001293214.2:c.728C>T	NP_001280143.1:p.Pro243Leu	missense
NM_001293215.2:c.644C>T	NP_001280144.1:p.Pro215Leu	missense
NM_001293216.2:c.644C>T	NP_001280145.1:p.Pro215Leu	missense
NC_000006.12:g.30723922C>T
NC_000006.11:g.30691699C>T
NG_034142.1:g.8722C>T

... more HGVS ... less HGVS

Protein change

P287L, P307L, P215L, P243L

Other names

Canonical SPDI

NC_000006.12:30723921:C:T

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: CA363148899 dbSNP: rs1554202416 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	102	109

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.
not provided	Likely pathogenic (1)	criteria provided, single submitter	May 14, 2018	RCV000657977.1
Complex cortical dysplasia with other brain malformations 6	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Oct 12, 2022	RCV000656087.3
Lissencephaly	Likely pathogenic (1)	no assertion criteria provided	-	RCV001291303.1
Multiple benign circumferential skin creases on limbs 1	Pathogenic (1)	criteria provided, single submitter	Oct 12, 2022	RCV003147489.1
Seizure	Pathogenic (1)	criteria provided, single submitter	Nov 23, 2022	RCV004551640.2

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.
Uncertain significance (Sep 01, 2017)	criteria provided, single submitter (Wiszniewski et al. (Eur J Hum Genet. 2018)) Method: research	Complex cortical dysplasia with other brain malformations 6 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine Accession: SCV000598585.1 First in ClinVar: Jun 02, 2018 Last updated: Jun 02, 2018	Publications: PubMed (1) PubMed: 29706646 Comment: this variant was indentified in an individual with malformations of cortical development Number of individuals with the variant: 1 Clinical Features: Abnormality of neuronal migration (present) Method: WES
Likely pathogenic (May 14, 2018)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000779748.2 First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018	Comment: The P287L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P287L … (more) The P287L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P287L variant is not observed in large population cohorts (Lek et al., 2016). The P287L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret P287L as a likely pathogenic variant. (less)
Pathogenic (Oct 12, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Multiple benign circumferential skin creases on limbs 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV003835503.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Pathogenic (Oct 12, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Complex cortical dysplasia with other brain malformations 6 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV003835774.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Pathogenic (Nov 23, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Seizures Affected status: yes Allele origin: de novo	Génétique des Maladies du Développement, Hospices Civils de Lyon Accession: SCV005043049.1 First in ClinVar: May 19, 2024 Last updated: May 19, 2024	Sex: female
Likely pathogenic (-)	no assertion criteria provided Method: research	lissencephaly Affected status: yes Allele origin: de novo	University of Washington Center for Mendelian Genomics, University of Washington Accession: SCV001479775.1 First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021	Publications: PubMed (1) PubMed: 29671837

Comment:

The P287L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P287L variant is not observed in large population cohorts (Lek et al., 2016). The P287L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret P287L as a likely pathogenic variant.

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
Comprehensive genomic analysis of patients with disorders of cerebral cortical development.	Wiszniewski W	European journal of human genetics : EJHG	2018	PMID: 29706646
Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly.	Di Donato N	Genetics in medicine : official journal of the American College of Medical Genetics	2018	PMID: 29671837

Text-mined citations for rs1554202416 ...

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 Jun 23, 2024

ClinVar Genomic variation as it relates to human health

NM_178014.4(TUBB):c.860C>T (p.Pro287Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1554202416 ...