rs587780494

Variant summary

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

The NM_001267550.2(TTN):c.6555_6556insTGTAAGGAAACAGACA(p.Lys2186CysfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

TTN
NM_001267550.2 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:3

Conservation

PhyloP100: 1.95

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 2-178775155-T-TTGTCTGTTTCCTTACA is Pathogenic according to our data. Variant chr2-178775155-T-TTGTCTGTTTCCTTACA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130679.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=3, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.6555_6556insTGTAAGGAAACAGACA	p.Lys2186CysfsTer15	frameshift_variant	29/363	ENST00000589042.5
TTN	NM_133379.5 linkuse as main transcript	c.6555_6556insTGTAAGGAAACAGACA	p.Lys2186CysfsTer15	frameshift_variant	29/46	ENST00000360870.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000360870.10 linkuse as main transcript	c.6555_6556insTGTAAGGAAACAGACA	p.Lys2186CysfsTer15	frameshift_variant	29/46	5	NM_133379.5		Q8WZ42-6
TTN	ENST00000589042.5 linkuse as main transcript	c.6555_6556insTGTAAGGAAACAGACA	p.Lys2186CysfsTer15	frameshift_variant	29/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1 linkuse as main transcript	n.2582_2583insTGTCTGTTTCCTTACA		non_coding_transcript_exon_variant	12/13

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250662

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135452

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461698

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

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:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 10, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2021	Reported in association with early-onset atrial fibrillation in a whole-genome sequencing cohort (Choi et al., 2018); Reported in ClinVar (ClinVar Variant ID# 130679; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 30535219) -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Oct 06, 2021	- -

Dilated cardiomyopathy 1G

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jul 11, 2023

The TTN c.6555_6556insTGTAAGGAAACAGACA (p.Lys2186CysfsTer15) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant is located in exon 29 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 = 19.0) (PMID: 27869827). This variant is reported in the Genome Aggregation Database in seven alleles at a frequency of 0.000054 in the European (non-Finnish) population (version 2.1.1). Based on the available evidence, the c.6555_6556insTGTAAGGAAACAGACA (p.Lys2186CysfsTer15) variant is classified as likely pathogenic for dilated cardiomyopathy. -

Tibial muscular dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 30, 2013

- -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2023

The c.6417_6418ins16 variant, located in coding exon 27 of the TTN gene, results from an insertion of 16 nucleotides (TGTAAGGAAACAGACA) at position 6417, causing a translational frameshift with a predicted alternate stop codon (p.K2140Cfs*15). 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 (referred to as p.Lys2186fs) has been detected in an early-onset atrial fibrillation cohort (Choi SH et al. JAMA. 2018 12;320(22):2354-2364). 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). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 02, 2018

This sequence change results in a premature translational stop signal in the TTN gene (p.Lys2186Cysfs*15).Â¬â€ 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 ExAC database. This variant has been observed to segregate with dilated cardiomyopathyÂ¬â€ in a family (Invitae).Â¬â€ ClinVar contains an entry for this variant (Variation ID: 130679). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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