12-114394817-G-T

Position:

• chr12-114394817-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_181486.4(TBX5):​c.587C>A​(p.Ser196Ter) variant causes a stop gained change involving the alteration of a 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBX5 NM_181486.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.60

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-114394817-G-T is Pathogenic according to our data. Variant chr12-114394817-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 279906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-114394817-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX5	NM_181486.4	c.587C>A	p.Ser196Ter	stop_gained	6/9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.587C>A	p.Ser196Ter	stop_gained	6/9		NP_000183.2
TBX5	NM_080717.4	c.437C>A	p.Ser146Ter	stop_gained	5/8		NP_542448.1
TBX5	XM_017019912.2	c.635C>A	p.Ser212Ter	stop_gained	6/9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7	c.587C>A	p.Ser196Ter	stop_gained	6/9	1	NM_181486.4	ENSP00000384152	P1
TBX5	ENST00000310346.8	c.587C>A	p.Ser196Ter	stop_gained	6/9	1		ENSP00000309913	P1
TBX5	ENST00000349716.9	c.437C>A	p.Ser146Ter	stop_gained	5/8	1		ENSP00000337723
TBX5	ENST00000526441.1	c.587C>A	p.Ser196Ter	stop_gained	5/7	1		ENSP00000433292

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Holt-Oram syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 10, 2021	- -
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	Jan 11, 2024	Identified in additional patients with Holt-Oram syndrome in published literature (PMID: 16183809, 12789647, 10077612, 17534187); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25623069, 25525159, 34159885, 15710732, 8988164, 16183809, 25263169, 12789647, 10077612, 17534187) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jan 16, 2023	- -

Aortic valve disease 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2023

This sequence change creates a premature translational stop signal (p.Ser196*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Holt-Oran syndrome (PMID: 8988164, 10077612, 12789647, 15710732, 17534187). This variant is also known as c.1243C>A. ClinVar contains an entry for this variant (Variation ID: 279906). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2024

The c.587C>A (p.S196*) alteration, located in exon 6 (coding exon 5) of the TBX5 gene, consists of a C to A substitution at nucleotide position 587. This changes the amino acid from a serine (S) to a stop codon at amino acid position 196. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in multiple individuals with features consistent with Holt-Oram syndrome (Basson, 1999; Brassington, 2003; McDermott, 2005; Debeer, 2007) and has been determined to be the result of a de novo mutation or germline mosaicism in two families (Li, 1997; Sobh, 2022). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.97
GERP RS		5.8

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: rs886041247; hg19: chr12-114832622;