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NM_178014.4(TUBB):c.1198G>C (p.Gly400Arg) AND Congenital fibrosis of extraocular muscles

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Mar 13, 2024
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:
RCV003984294.3

Allele description [Variation Report for NM_178014.4(TUBB):c.1198G>C (p.Gly400Arg)]

NM_178014.4(TUBB):c.1198G>C (p.Gly400Arg)

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.1198G>C (p.Gly400Arg)
Other names:
NR_120608.2:n.754G>C
HGVS:
  • NC_000006.12:g.30724260G>C
  • NG_034142.1:g.9060G>C
  • NM_001293212.2:c.1258G>C
  • NM_001293213.2:c.592G>C
  • NM_001293214.2:c.1066G>C
  • NM_001293215.2:c.982G>C
  • NM_001293216.2:c.982G>C
  • NM_178014.4:c.1198G>CMANE SELECT
  • NP_001280141.1:p.Gly420Arg
  • NP_001280142.1:p.Gly198Arg
  • NP_001280143.1:p.Gly356Arg
  • NP_001280144.1:p.Gly328Arg
  • NP_001280145.1:p.Gly328Arg
  • NP_821133.1:p.Gly400Arg
  • NC_000006.11:g.30692037G>C
  • NR_120608.2:n.754G>C
Protein change:
G198R
Molecular consequence:
  • NM_001293212.2:c.1258G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293213.2:c.592G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293214.2:c.1066G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293215.2:c.982G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001293216.2:c.982G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_178014.4:c.1198G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_120608.2:n.754G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Congenital fibrosis of extraocular muscles
Identifiers:
MONDO: MONDO:0007614; MedGen: C1302995; OMIM: PS135700; Human Phenotype Ontology: HP:0001491

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004800967Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Mar 13, 2024) 		germlinecuration

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

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

Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders.

Jurgens JA, Barry BJ, Chan WM, MacKinnon S, Whitman MC, Matos Ruiz PM, Pratt BM, England EM, Pais L, Lemire G, Groopman E, Glaze C, Russell KA, Singer-Berk M, Di Gioia SA, Lee AS, Andrews C, Shaaban S, Wirth MM, Bekele S, Toffoloni M, Bradford VR, et al.

Genet Med. 2024 Jul 17:101216. doi: 10.1016/j.gim.2024.101216. [Epub ahead of print]

PubMed [citation]
PMID:
39033378

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV004800967.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (2)

Description

The heterozygous p.Gly400Arg variant in TUBB was identified by our study in one individual with congenital fibrosis of the extraocular muscles and attention deficit disorder, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). The p.Gly400Arg variant in TUBB has not been previously reported in individuals with TUBB-related disease. This variant was absent from large population studies. The number of missense variants reported in TUBB in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. The p.Gly400Arg variant is located in a region of TUBB that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 23246003). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Gly400Arg variant is uncertain. ACMG/AMP Criteria applied: PM1_Supporting, PM2_Supporting, PP2, PP3 (Richards 2015).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Aug 18, 2024