chr2-178630250-G-A

Variant names:

• chr2-178630250-G-A
• rs140743001
• NM_001267550.2:c.44272C>T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

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 Likely pathogenic (★★). 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12 U:2
• Conservation: PhyloP100: 2.74

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-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]

ACMG classification

Verdict is Pathogenic. Variant got 16 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 [Likely_pathogenic]. Clinvar id is 202367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178630250-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.44272C>T	p.Arg14758*	stop_gained	Exon 239 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.44272C>T	p.Arg14758*	stop_gained	Exon 239 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151846 Hom.: 0 Cov.: 33

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: 2 AN: 248384 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134732

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: 11 AN: 1460806 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 726678

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: 3 AN: 151964 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74236

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: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:12 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3 Uncertain:1

Mar 18, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Located in a specific region of the I-band within TTN for which truncating variants are significantly associated with autosomal dominant cardiomyopathy and also with autosomal recessive skeletal myopathies (PMID: 27625338, 27869827, 32778822); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22335739, 24503780, 30333491, 33874732, 33106378, 31737537, 33500567, 31112426, 33996946, 27532257, 27625338, 27869827, 32778822, 37728764, 31691645, 36264615, 37652022) -

Feb 12, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1G Pathogenic:3

Jun 30, 2023

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 06, 2024

Cardiogenetics and Myogenetics Molecular and Cellular Functional Unit, Aphp Sorbonne University-Hopital Pitie Salpetriere

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 16, 2016

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:2

Oct 27, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 04, 2024

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS4_mod, PM2, PP5 -

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

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; internal data). 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, internal data). 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, internal data). For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy Pathogenic:1

Nov 27, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Autosomal recessive titinopathy Pathogenic:1

Jan 16, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TTN c.36568C>T (p.Arg12190X; also known as c.44272C>T; p.Arg14758X on NM_001267550) 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. Loss of function variants in all TTN bands are strongly associated with a spectrum of autosomal recessive titinopathies when exon expression (proportion spliced in, PSI, 1=complete expression) in skeletal muscle is >0.1 (PMID: 36977548, 39198997, 29598826, 32778822, 29691892, 33449170, 36977548, internal data). In contrast, loss of function variants in all TTN bands are only strongly associated with autosomal dominant TTN-related cardiomyopathies if located in exons constitutively expressed (PSI >0.9) in cardiac muscle, excluding extreme C-terminal exons 359-363 (PMID: 25589632, 31216868, 32964742, 34662387, 27869827, Shetty et al., Nat Cardiovasc Res 2024, cardiodb.org, internal data). This variant has a maximum skeletal muscle PSI of 0.959 and a maximum cardiac muscle PSI of 1.0. The variant allele was found at a frequency of 8.1e-06 in 248384 control chromosomes (gnomAD). c.36568C>T has been reported in the literature in individuals affected with autosomal dominant cardiac conditions and autosomal recessive TTN-related conditions (examples: Vissing_JMG_2021, Goli_Circulation_2021, Xiao_FCM_2021, internal data). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 33106378, 33874732, 33996946). ClinVar contains an entry for this variant (Variation ID: 202367). Based on the evidence outlined above, the variant was classified as likely pathogenic for both autosomal dominant and autosomal recessive TTN-related conditions. -

Primary dilated cardiomyopathy Pathogenic:1

Jun 03, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Uncertain:1

May 06, 2020

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

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	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	54
DANN	Benign	0.97
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.91	D
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

Other links and lift over

dbSNP: rs140743001; hg19: chr2-179494977; COSMIC: COSV60241826; COSMIC: COSV60241826;