rs775186117

Variant names:

• chr2-178617393-G-A
• rs775186117
• NM_001267550.2:c.47692C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178617393-G-A
• chr2-178617393-G-C
• chr2-178617393-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001267550.2(TTN):​c.47692C>T​(p.Arg15898*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,437,602 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R15898R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TTN NM_001267550.2 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.16
• Publications: 1 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 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 2-178617393-G-A is Pathogenic according to our data. Variant chr2-178617393-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 223371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.47692C>T	p.Arg15898*	stop_gained	Exon 254 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.42769C>T	p.Arg14257*	stop_gained	Exon 204 of 313	NP_001243779.1
	TTN	NM_133378.4		c.39988C>T	p.Arg13330*	stop_gained	Exon 203 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.47692C>T	p.Arg15898*	stop_gained	Exon 254 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.47536C>T	p.Arg15846*	stop_gained	Exon 252 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.47416C>T	p.Arg15806*	stop_gained	Exon 252 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000459 AC: 1 AN: 217976 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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000100

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1437602 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 713518

African (AFR) AF: 0.00 AC: 0 AN: 32282

American (AMR) AF: 0.00 AC: 0 AN: 39552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25328

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39094

South Asian (SAS) AF: 0.00 AC: 0 AN: 80582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1102886

Other (OTH) AF: 0.00 AC: 0 AN: 59432

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000831 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1G Pathogenic:2

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

KTest Genetics, KTest

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg15898*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 25589632, 29961767). ClinVar contains an entry for this variant (Variation ID: 223371). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

not provided Pathogenic:1

Aug 04, 2019

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Primary dilated cardiomyopathy Pathogenic:1

Oct 08, 2014

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This TTN truncating variant (TTNtv) was identified in one individual in this cohort and is located in an exon that is highly expressed in the heart. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart.

Cardiovascular phenotype Pathogenic:1

Mar 26, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.20497C>T (p.R6833*) alteration, located in exon 82 (coding exon 81) of the TTN gene, consists of a C to T substitution at nucleotide position 20497. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 6833. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The TTN c.20497C>T alteration failed random forest filters in the Genome Aggregation Database (gnomAD). This variant (also referred to as NM_001267550.1:c.47692C>T, p.R15898*) was reported in an individual with features consistent with dilated cardiomyopathy (Roberts, 2015; Minoche, 2019). 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%). Based on the available evidence, this alteration is classified as likely pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	51
DANN	Uncertain	0.98
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.71	D
PhyloP100		1.2
Vest4		0.96
GERP RS		0.77
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: rs775186117; hg19: chr2-179482120; COSMIC: COSV60000160; COSMIC: COSV60000160;