12-114366312-G-A

Position:

• chr12-114366312-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_181486.4(TBX5):​c.835C>T​(p.Arg279*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBX5 NM_181486.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 2.55

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.464 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-114366312-G-A is Pathogenic according to our data. Variant chr12-114366312-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 213832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-114366312-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX5	NM_181486.4	c.835C>T	p.Arg279*	stop_gained	8/9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.835C>T	p.Arg279*	stop_gained	8/9		NP_000183.2
TBX5	NM_080717.4	c.685C>T	p.Arg229*	stop_gained	7/8		NP_542448.1
TBX5	XM_017019912.2	c.883C>T	p.Arg295*	stop_gained	8/9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7	c.835C>T	p.Arg279*	stop_gained	8/9	1	NM_181486.4	ENSP00000384152.3
TBX5	ENST00000310346.8	c.835C>T	p.Arg279*	stop_gained	8/9	1		ENSP00000309913.4
TBX5	ENST00000349716.9	c.685C>T	p.Arg229*	stop_gained	7/8	1		ENSP00000337723.5
TBX5	ENST00000526441.1	c.835C>T	p.Arg279*	stop_gained	7/7	1		ENSP00000433292.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Holt-Oram syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Jun 14, 2019	ACMG codes: PVS1, PM2, PP4, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 02, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000213832, PMID:8988164). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	clinical testing	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	Jun 14, 2018	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2024	In vitro studies on cardiac tissue harboring R279X show significantly decreased TBX5 transcript levels compared to wild type (PMID: 24664498); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21637475, 34930662, 24664498, 8988164, 25525159, 25263169, 15710732, 12789647, 28855170, 31215120, 32449309, 19204083) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2018	- -

TBX5-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2024

The TBX5 c.835C>T variant is predicted to result in premature protein termination (p.Arg279*). This variant has been reported in multiple unrelated individuals with Holt-Oram syndrome and Tetralogy of Fallot, and has been documented as a de novo finding (Baban et al. 2014. PubMed ID: 25263169; Bowling et al. 2021. PubMed ID: 34930662). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in TBX5 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Aortic valve disease 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 07, 2023

This sequence change creates a premature translational stop signal (p.Arg279*) in the TBX5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TBX5 are known to be pathogenic (PMID: 16183809, 16917909). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 213832). This premature translational stop signal has been observed in individual(s) with Holt-Oram syndrome (HOS) and Tetralogy of Fallot (TOF) (PMID: 21637475, 24664498, 25263169). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.91	D
Vest4		0.97
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs863223788; hg19: chr12-114804117; COSMIC: COSV59862842;