rs545954490

Variant names:

• chr2-178569478-G-A
• rs545954490
• NM_001267550.2:c.76654C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178569478-G-A
• chr2-178569478-G-C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001267550.2(TTN):​c.76654C>T​(p.Arg25552*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000372 in 1,612,640 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 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TTN NM_001267550.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.81
• Publications: 5 publications found

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

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-178569478-G-A is Pathogenic according to our data. Variant chr2-178569478-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 404828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569478-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 404828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569478-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 404828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569478-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 404828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569478-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 404828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569478-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 404828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569478-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 404828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569478-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 404828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569478-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 404828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569478-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 404828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569478-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 404828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569478-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 404828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569478-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 404828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569478-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 404828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569478-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 404828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569478-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 404828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569478-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 404828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569478-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 404828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569478-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 404828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178569478-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 404828.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
TTN	NM_001267550.2	c.76654C>T	p.Arg25552*	stop_gained	Exon 326 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.76654C>T	p.Arg25552*	stop_gained	Exon 326 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152026 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 247864 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000561

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460496 Hom.: 0 Cov.: 40 AF XY: 0.00000551 AC XY: 4 AN XY: 726398

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.00 AC: 0 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111132

Other (OTH) AF: 0.00 AC: 0 AN: 60312

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152144 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74376

African (AFR) AF: 0.0000241 AC: 1 AN: 41536

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Dec 10, 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.Arg25552*) 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 (rs545954490, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with clinical features of dilated cardiomyopathy (PMID: 30847666; internal data). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg22984*. ClinVar contains an entry for this variant (Variation ID: 404828). This variant is located in the A band of TTN (PMID: 25589632). Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy (PMID: 25589632). Truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). For these reasons, this variant has been classified as Pathogenic. -

Dilated cardiomyopathy 1G Pathogenic:1

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is known mechanism of disease in this gene. In addition, dominant-negative is also a suggested mechanism. (PMID: 25589632). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Variants in this gene that result in a premature truncating codon (PTC) are known to have reduced penetrance in DCM (PMID: 25589632). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is located in the annotated C-terminal A-band and the exon has a PSI score of 100 (PMID: 25589632). (I) 0703 - Other NMD predicted variants comparable to the one identified in this case have moderate previous evidence for pathogenicity (ClinVar). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as likely pathogenic in individuals with cardiomyopathy (ClinVar, PMID: 30847666). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy Pathogenic:1

Nov 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Dec 27, 2018

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Apr 21, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R16487* variant (also known as c.49459C>T), located in coding exon 153 of the TTN gene, results from a C to T substitution at nucleotide position 49459. This changes the amino acid from an arginine to a stop codon within coding exon 153. This exon is located in the A-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 NM_133378.4:c.68950C>T, p.Arg22984* and NM_001256850.1:c.71731C>T, p.Arg23911Ter) has been detected in an individual with unspecified cardiomyopathy, and in an individual with idiopathic dilated cardiomyopathy (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Trachoo O et al. PLoS One. 2022 Sep;17(9):e0267770). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This variant 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 (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; Akhtar MM et al. Circ Heart Fail, 2020 Oct;13:e006832; Massier M et al. Clin Genet, 2025 Jan). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	65
DANN	Uncertain	0.97
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		5.8
Vest4		0.94
GERP RS		4.7
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs545954490; hg19: chr2-179434205; COSMIC: COSV59876512;