chr2-178630250-G-A

Position:

chr2-178630250-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5

The NM_001267550.2(TTN):c.44272C>T(p.Arg14758*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,612,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

TTN
NM_001267550.2 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11U:2

Conservation

PhyloP100: 2.74

Variant links:

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

TTN links:

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

TTN-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 2-178630250-G-A is Pathogenic according to our data. Variant chr2-178630250-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 202367.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=2, Likely_pathogenic=6}. Variant chr2-178630250-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2 link	c.44272C>T	p.Arg14758*	stop_gained	239/363	ENST00000589042.5	NP_001254479.2	A0A0A0MTS7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5 link	c.44272C>T	p.Arg14758*	stop_gained	239/363	5	NM_001267550.2	ENSP00000467141.1		A0A0A0MTS7

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151846

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000805

AC:

AN:

248384

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134732

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1460806

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726678

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000810

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

151964

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74236

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000828

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:11Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jul 30, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2023	Reported in association with DCM, LVNC and familial atrial fibrillation (PMID: 27532257, 30333491, 31737537, 33500567, 33106378, 33996946, 36264615); Not observed at significant frequency in large population cohorts (gnomAD); Located in a region of TTN within the I-band in which the majority of loss of function variants are significantly associated with autosomal dominant titinopathies (PMID: 27625338, 27869827); This variant is associated with the following publications: (PMID: 22335739, 24503780, 30333491, 33874732, 33106378, 31737537, 33500567, 31112426, 27625338, 27869827, 33996946, 27532257, 36264615) -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 12, 2016	- -

Dilated cardiomyopathy 1G

Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Cardiogenetics and Myogenetics Molecular and Cellular Functional Unit, Aphp Sorbonne University-Hopital Pitie Salpetriere	Jan 06, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Nov 16, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 30, 2023	The TTN c.44272C>T (p.Arg14758Ter) is a nonsense variant, located in exon 239 of the meta transcript of titin within the I-band, which is highly expressed in cardiac tissue (PMID:25589632). In a meta-analysis of TTN truncating variants in DCM patients and controls, variants in this region were associated with a significantly increased risk of developing DCM (odds ratio 19.5) (PMID:27869827). The p.Arg14758Ter variant has been reported in the literature in one patient with dilated cardiomyopathy (PMID:27532257). This variant is reported in the Genome Aggregation Database in three alleles at a frequency of 0.000026 in the Total population (version 3.1.2). Based on the available evidence the c.44272C>T (p.Arg14758Ter) variant is classified as likely pathogenic for dilated cardiomyopathy. -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 12, 2023

This sequence change creates a premature translational stop signal (p.Arg14758*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is present in population databases (rs140743001, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy and/or left ventricular noncompaction (PMID: 27532257, 31737537, 33500567, 33874732; Invitae). ClinVar contains an entry for this variant (Variation ID: 202367). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742). For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 27, 2024

The c.39349C>T variant in TTN (NM_001256850.1) leads to premature stop codon at position 13117, which is predicted to lead to a truncated or absent protein. This variant has also been referred to as c.44272C>T, p.R14758X using alternate nomenclature. It was identified in 2/248384 (0.0008%) of alleles tested from control populations in the Genome Aggregation Database (gnomAD), was reported in 0.003% of Admixed American individuals, and is considered to be a rare variant. It has been previously reported in >5 apparently unrelated individuals with dilated, left ventricular non-compaction, atrial fibrillation, peripartum, or unspecified cardiomyopathy (PMID 27532257, 31737537, 33106378, 33996946, 36264615, 30333491, 33874732, ClinVar database, CHEO internal database). This variant is located in the proximal I-band in a highly expressed exon, where Titin truncating variants are very strongly associated with dilated cardiomyopathy (PMID 27625338, 26439713, 25589632). This variant is listed in ClinVar (VCV000202367). Based on the above information, we categorize this variant as pathogenic. -

Primary dilated cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 03, 2016

The p.Arg12190X variant in TTN has been identified by our laboratory in 1 Caucas ian individual with DCM and 1 Caucasian individual with LVNC (LMM data). This va riant has also been identified in 1/67564 European chromosomes by the Exome Aggr egation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs140743001). Th is nonsense variant leads to a premature termination codon at position 12190, wh ich is predicted to lead to a truncated or absent protein. Nonsense and other tr uncating variants in TTN are strongly associated with DCM if they are located in the exons encoding for the A-band (Herman 2012, Pugh 2014) and/or are located i n an exon that is highly expressed in the heart (Roberts 2015). The p.Arg12190X variant is located in I-band in the highly expressed exon 188. In summary, alth ough additional studies are required to fully establish its clinical significanc e, the p.Arg12190X variant is likely pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2024

The p.R5693* variant (also known as c.17077C>T), located in coding exon 66 of the TTN gene, results from a C to T substitution at nucleotide position 17077. This changes the amino acid from an arginine to a stop codon within coding exon 66. This exon is located in the I-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). This variant (also referred to as p.R14758X, c.44272C>T and 2:179494977G>A) has been detected in cohorts reported to have atrial fibrillation, peripartum cardiomyopathy, left ventricular non-compaction cardiomyopathy, dilated cardiomyopathy (DCM) or who underwent genetic testing for DCM (Walsh R et al. Genet. Med., 2017 02;19:192-203; Vissing CR et al. J Med Genet. 2021 Dec;58(12):832-841; Goli R et al. Circulation. 2021 May;143(19):1852-1862; Mazzarotto F et al. Genet Med. 2021 May;23(5):856-864). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. While truncating variants in TTN are present in 1-3% of the general population, truncating variants in the A-band are the most common cause of dilated cardiomyopathy (DCM) (Herman DS et al. N. Engl. J. Med., 2012 Feb;366:619-28; Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6). TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM regardless of their position in titin (Schafer S et al. Nat. Genet., 2017 01;49:46-53). As such, this alteration is classified as likely pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 06, 2020

The c.36568C>T sequence change results in the creation of a premature stop codon at amino acid position 12190, p.Arg12190*. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated TTN protein with potentially abnormal function. This variant is present in 2 individuals in gnomAD with an overall population frequency of 0.008% (rs140743001). This variant has also been reported in an individual with dilated cardiomyopathy (PMID: 27532257). This variant is present in ClinVar and has been classified as either a variant of unknown significance or likely pathogenic by several clinical laboratories (Variation ID: 202367). The Arg12190* variant is located in one of the constitutive exons in the distal I-band region. Truncating variants in this region have been reported in individuals with autosomal recessive centronuclear myopathy (PMID: 23975875) however truncating TTN variants have been reported in approximately 3% of control alleles (PMIDs: 22335739, 26701604). Due to these contrasting evidences, the clinical significance of the p.Arg12190* change remains unknown at this time. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Benign

0.97

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.91

Vest4

0.94

GERP RS

3.1

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

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