chr2-178667239-C-A

Variant names:

• chr2-178667239-C-A
• rs878854299
• NM_001267550.2:c.35794G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_001267550.2(TTN):​c.35794G>T​(p.Glu11932*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000188 in 1,596,686 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: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: TTN NM_001267550.2 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: -1.82
• Publications: 0 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-178667239-C-A is Pathogenic according to our data. Variant chr2-178667239-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 238750.

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.35794G>T	p.Glu11932*	stop_gained	Exon 162 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.34264+2979G>T		intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.31483+2979G>T		intron	N/A	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.35794G>T	p.Glu11932*	stop_gained	Exon 162 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.35794G>T	p.Glu11932*	stop_gained	Exon 162 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.35518G>T	p.Glu11840*	stop_gained	Exon 160 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152040 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000916 AC: 2 AN: 218240 AF XY: 0.00000839

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: 0.0000212

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000187 AC: 27 AN: 1444646 Hom.: 0 Cov.: 31 AF XY: 0.0000153 AC XY: 11 AN XY: 716992

African (AFR) AF: 0.00 AC: 0 AN: 33196

American (AMR) AF: 0.00 AC: 0 AN: 42900

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25672

East Asian (EAS) AF: 0.00 AC: 0 AN: 39242

South Asian (SAS) AF: 0.00 AC: 0 AN: 83374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.0000245 AC: 27 AN: 1103302

Other (OTH) AF: 0.00 AC: 0 AN: 59714

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152040 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74264

African (AFR) AF: 0.00 AC: 0 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67966

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Aug 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 06, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 15, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed with a splice variant on the opposite allele (in trans) in a patient with a congenital TTN-related disorder in published literature (Oates et al., 2018); Nonsense variant predicted to result in protein truncation or nonsense mediated decay; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32778822, 29691892)

Autosomal recessive limb-girdle muscular dystrophy type 2J Pathogenic:1

Feb 01, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 04, 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.Glu11932*) 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 clinical features of autosomal recessive centronuclear myopathy (PMID: 29691892). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant has been reported in individual(s) with autosomal dominant non-ischemic cardiomyopathy (internal data); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 238750). 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.

Early-onset myopathy with fatal cardiomyopathy Pathogenic:1

Jan 09, 2025

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous p.Glu11932Ter variant in TTN was identified by our study in one individual with early onset myopathy, in the compound heterozygous state along with another pathogenic variant. The phase of these variants is unknown at this time. The p.Glu11932Ter variant has been reported in 6 families with TTN-related myopathy (PMID: 29691892), and has been identified in 0.003% (30/1171268) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs878854299). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of the 7 affected individuals, 4 were compound heterozygotes that carried a reported pathogenic or likely pathogenic variant in trans, which increases the likelihood that the p.Glu11932Ter variant is pathogenic (Variation ID: 1067510, 2938083, 404786, 223329; PMID: 29691892). This variant has also been reported in ClinVar (Variation ID: 238750) and has been interpreted as pathogenic/likely pathogenic by Labcorp, GeneDx, MGZ Medical Genetics Center, and CeGaT Center for Human Genetics Tuebingen, and as a variant of uncertain significance by Eurofins Ntd Llc. This nonsense variant leads to a premature termination codon at position 11932 which is predicted to lead to a truncated or absent protein. Loss of function of the TTN gene is an established disease mechanism in autosomal recessive TTN-related myopathy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive TTN-related myopathy. ACMG/AMP Criteria applied: PM3_very-strong, PVS1, PM2_supporting (Richards 2015).

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

May 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.10	N
PhyloP100		-1.8
Vest4		0.74
GERP RS		0.21
PromoterAI		-0.012	Neutral
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs878854299; hg19: chr2-179531966;