NM_181486.4(TBX5):c.192G>A (p.Trp64Ter) AND Holt-Oram syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 11, 2019
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:: RCV001193147.1

Allele description [Variation Report for NM_181486.4(TBX5):c.192G>A (p.Trp64Ter)]

NM_181486.4(TBX5):c.192G>A (p.Trp64Ter)

Gene:

TBX5:T-box transcription factor 5 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q24.21

Genomic location:

Preferred name:

NM_181486.4(TBX5):c.192G>A (p.Trp64Ter)

HGVS:

NC_000012.12:g.114401876C>T
NG_007373.1:g.11567G>A
NM_000192.3:c.192G>A
NM_080717.4:c.42G>A
NM_181486.4:c.192G>AMANE SELECT
NP_000183.2:p.Trp64Ter
NP_542448.1:p.Trp14Ter
NP_852259.1:p.Trp64Ter
LRG_670t1:c.192G>A
LRG_670:g.11567G>A
LRG_670p1:p.Trp64Ter
NC_000012.11:g.114839681C>T

Protein change:

W14*

Links:

dbSNP: rs1555226581

NCBI 1000 Genomes Browser:

rs1555226581

Molecular consequence:

NM_000192.3:c.192G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_080717.4:c.42G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_181486.4:c.192G>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Holt-Oram syndrome (HOS)
Synonyms:: Ventriculo-radial syndrome; Atrio digital syndrome; Cardiac-limb syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007732; MedGen: C0265264; Orphanet: 392; OMIM: 142900

Recent activity

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Mus musculus reticulon 4 (Rtn4), transcript variant 5, mRNA
Mus musculus reticulon 4 (Rtn4), transcript variant 5, mRNA
gi|34610236|ref|NM_194051.1|

Nucleotide
Mus musculus plexin A3, mRNA (cDNA clone MGC:118733 IMAGE:30945372), complete cd...
Mus musculus plexin A3, mRNA (cDNA clone MGC:118733 IMAGE:30945372), complete cds
gi|146141256|gb|BC093482.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001361815	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Feb 11, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001361815

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Feb 11, 2019)

germline

clinical testing

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

Citation Link

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Summary from all submissions

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

Citations

PubMed

Novel TBX5 mutations and molecular mechanism for Holt-Oram syndrome.

Fan C, Duhagon MA, Oberti C, Chen S, Hiroi Y, Komuro I, Duhagon PI, Canessa R, Wang Q.

J Med Genet. 2003 Mar;40(3):e29. No abstract available.

PubMed [citation]

PMID:: 12624158
PMCID:: PMC1618877

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001361815.1

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

Description

Variant summary: TBX5 c.192G>A (p.Trp64X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 246266 control chromosomes (gnomAD). A different variant leading to the same protein level change (c.191G>A (p.Trp64X)) has been reported in the literature in an individual affected with Holt-Oram Syndrome (Fan 2003; of note, while the authors described this variant as c.192G>A, their sequence data confirms that it was c.191G>A). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

Last Updated: Jun 23, 2024

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