rs104894382

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_181486.4(TBX5):c.709C>T(p.Arg237Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R237Q) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

TBX5
NM_181486.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 5.26

Variant links:

Genes affected

TBX5 (HGNC:11604): (T-box transcription factor 5) This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene is closely linked to related family member T-box 3 (ulnar mammary syndrome) on human chromosome 12. The encoded protein may play a role in heart development and specification of limb identity. Mutations in this gene have been associated with Holt-Oram syndrome, a developmental disorder affecting the heart and upper limbs. Several transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

TBX5 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a DNA_binding_region T-box (size 180) in uniprot entity TBX5_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_181486.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-114385521-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.96

PP5

Variant 12-114385522-G-A is Pathogenic according to our data. Variant chr12-114385522-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX5	NM_181486.4 link	c.709C>T	p.Arg237Trp	missense_variant	Exon 7 of 9	ENST00000405440.7	NP_852259.1	Q99593-1
TBX5	NM_000192.3 link	c.709C>T	p.Arg237Trp	missense_variant	Exon 7 of 9		NP_000183.2	Q99593-1
TBX5	NM_080717.4 link	c.559C>T	p.Arg187Trp	missense_variant	Exon 6 of 8		NP_542448.1	Q99593-3
TBX5	XM_017019912.2 link	c.757C>T	p.Arg253Trp	missense_variant	Exon 7 of 9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TBX5	ENST00000405440.7 link	c.709C>T	p.Arg237Trp	missense_variant	Exon 7 of 9	1	NM_181486.4	ENSP00000384152.3	Q99593-1
TBX5	ENST00000310346.8 link	c.709C>T	p.Arg237Trp	missense_variant	Exon 7 of 9	1		ENSP00000309913.4	Q99593-1
TBX5	ENST00000349716.9 link	c.559C>T	p.Arg187Trp	missense_variant	Exon 6 of 8	1		ENSP00000337723.5	Q99593-3
TBX5	ENST00000526441.1 link	c.709C>T	p.Arg237Trp	missense_variant	Exon 6 of 7	1		ENSP00000433292.1	Q99593-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Holt-Oram syndrome

Pathogenic:2

Jun 14, 2018

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 16, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aortic valve disease 2

Pathogenic:1

Sep 11, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in individuals affected with Holt‚ÄìOram syndrome (PMID: 10077762, 12789647) and in a family affected with congenital heart defects (PMID: 25931334). ClinVar contains an entry for this variant (Variation ID: 7995). This missense change locates in the T-box domain of TBX5 and has been shown in experimental studies to affect TBX5 DNA-binding and TBX5 interaction with NKX2-5, resulting in reduced activation of downstream targets (PMID: 20519243, 12499378, 16380715). This variant disrupts the p.Arg237 amino acid residue in TBX5. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 10077612, 12499378, 20519243), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 237 of the TBX5 protein (p.Arg237Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. -

Heart, malformation of

Pathogenic:1

Laboratory for Genetics of Human Development Center for Human Genetics, Catholic University of Leuven

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cardiovascular phenotype

Pathogenic:1

May 27, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R237W pathogenic mutation (also known as c.709C>T), located in coding exon 6 of the TBX5 gene, results from a C to T substitution at nucleotide position 709. The arginine at codon 237 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was initially reported in two probands with Holt-Oram syndrome (Brassington AM et al. Am J Hum Genet, 2003 Jul;73:74-85). This variant has also been detected in individuals and families with atrial and ventricular septal defects (Ambry internal data; Jia Y et al. Am J Med Genet A, 2015 Aug;167A:1822-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Another alteration at the same codon, p.R237Q (c.710G>A) has also been described in individuals with Holt-Oram syndrome (Basson CT et al. Nat. Genet., 1997 Jan;15:30-5; Debeer P et al. Clin. Orthop. Relat. Res., 2007 Sep;462:20-6; Vanlerberghe C et al. Eur. J. Hum. Genet., 2019 03;27:360-368). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

.;D;D;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.94

D;.;D;D

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.96

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.8

.;H;H;H

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-6.9

D;D;D;D

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

.;D;D;D

Vest4

0.97

MutPred

0.84

.;Loss of disorder (P = 0.0069);Loss of disorder (P = 0.0069);Loss of disorder (P = 0.0069);

MVP

0.99

MPC

1.9

ClinPred

1.0

GERP RS

5.3

Varity_R

0.96

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over