NM_178014.4(TUBB):c.897G>A (p.Met299Ile) AND not provided

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Sep 23, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001817889.4

Allele description [Variation Report for NM_178014.4(TUBB):c.897G>A (p.Met299Ile)]

NM_178014.4(TUBB):c.897G>A (p.Met299Ile)

Gene:

TUBB:tubulin beta class I [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6p21.33

Genomic location:

Preferred name:

NM_178014.4(TUBB):c.897G>A (p.Met299Ile)

HGVS:

NC_000006.12:g.30723959G>A
NG_034142.1:g.8759G>A
NM_001293212.2:c.957G>A
NM_001293213.2:c.370-79G>A
NM_001293214.2:c.765G>A
NM_001293215.2:c.681G>A
NM_001293216.2:c.681G>A
NM_178014.4:c.897G>AMANE SELECT
NP_001280141.1:p.Met319Ile
NP_001280143.1:p.Met255Ile
NP_001280144.1:p.Met227Ile
NP_001280145.1:p.Met227Ile
NP_821133.1:p.Met299Ile
NC_000006.11:g.30691736G>A
NM_178014.3:c.897G>A
NR_120608.2:n.453G>A

Protein change:

M227I

Links:

dbSNP: rs2127749712

NCBI 1000 Genomes Browser:

rs2127749712

Molecular consequence:

NM_001293213.2:c.370-79G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001293212.2:c.957G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293214.2:c.765G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293215.2:c.681G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001293216.2:c.681G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_178014.4:c.897G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_120608.2:n.453G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Gene ID:103218079

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002067315	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002067315

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 23, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

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

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV002067315.1

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

Description

This is a novel sequence change that is not present in population databases (gnomAD and ExAC). This particular amino acid change does not appear to have been described in the literature in other patients with TUBB -related disorders, however, a different pathogenic sequence change affecting the same amino acid residue (p.Met299Val) has been described in a patient with microcephaly, brainstem hypoplasia, focal polymicrogyria, localized band heterotopia, partial agenesis of corpus callosum, ID and severe motor and language delays (PMID: 23246003). Functional studies for the reported variant, p.Met299Val, were supportive of the impact on neuronal migration in murine brain tissue. Pathogenic variants in the TUBB gene have been associated with cortical brain malformations including simplified gyral patterns, cerebellar hypoplasia, cortical dysplasia and delayed psychomotor development (OMIM # 615771). Additionally, pathogenic variants in this gene have also been described in patients with congenital symmetrical circumferential skin creases phenotype (OMIM# 156610) which is characterized by circumferential skin creases, cleft palate, facial dysmorphism, growth retardation, and intellectual disability. PMID: 30738969 described a patient harboring a missense variant in this gene, but presenting with a milder phenotype than other patients carrying the same variant. The majority of pathogenic variants in this gene have been reported to be de novo with exception of a single familial case of circumferential skin creases Kunze type (CSC-KT) (PMID: 29427453).

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

Last Updated: Dec 24, 2023

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