NM_001070.5(TUBG1):c.1022G>A (p.Arg341Gln) AND Complex cortical dysplasia with other brain malformations 4

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 3, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001809474.5

Allele description [Variation Report for NM_001070.5(TUBG1):c.1022G>A (p.Arg341Gln)]

NM_001070.5(TUBG1):c.1022G>A (p.Arg341Gln)

Gene:

TUBG1:tubulin gamma 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q21.2

Genomic location:

Preferred name:

NM_001070.5(TUBG1):c.1022G>A (p.Arg341Gln)

HGVS:

NC_000017.11:g.42614521G>A
NG_033886.1:g.10182G>A
NM_001070.5:c.1022G>AMANE SELECT
NP_001061.2:p.Arg341Gln
NC_000017.10:g.40766539G>A
NM_001070.4:c.1022G>A

Protein change:

R341Q

Links:

dbSNP: rs1555631467

NCBI 1000 Genomes Browser:

rs1555631467

Molecular consequence:

NM_001070.5:c.1022G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Complex cortical dysplasia with other brain malformations 4
Identifiers:: MONDO: MONDO:0014171; MedGen: C3809420; OMIM: 615412

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002058811	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002543794	Suma Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005042675	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	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

SCV002058811

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 3, 2022)

germline

clinical testing

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

SCV002543794

Suma Genomics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

de novo

clinical testing

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

SCV005042675

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

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	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	1	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 3billion, SCV002058811.1

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

Description

Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TUBG1 related disorder (ClinVar ID: VCV000452987, PS1_P). The variant was observed to be de novo (3billion dataset, PS2_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000373145, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.795, 3CNET: 0.963, PP3_P). A missense variant is a common mechanism associated with Cortical dysplasia (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Suma Genomics, SCV002543794.1

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

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

From Neuberg Centre For Genomic Medicine, NCGM, SCV005042675.1

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

Description

The missense variant c.1022G>Ap.Arg341Gln in TUBG1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. A different missense change c.1021C>Tp.Arg341Trp at the same codon has been reported as Pathogenic/Likely Pathogenic Yuen YTK, et al., 2019.The variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. However, study on multiple affected individuals and functional impact of the variant is not available.The amino acid Arginine at position 341 is changed to a Glutamine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg341Gln in TUBG1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.

#	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: Nov 10, 2024

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