rs752856716

Positions:

chr2-178632349-T-TA

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_001267550.2(TTN):c.43544_43545insT(p.Phe14516IlefsTer8) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000206 in 1,453,796 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V14515V) 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 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 4.41

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 Pathogenic. Variant got 11 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 2-178632349-T-TA is Pathogenic according to our data. Variant chr2-178632349-T-TA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 202536.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2 linkuse as main transcript	c.43544_43545insT	p.Phe14516IlefsTer8	frameshift_variant	236/363	ENST00000589042.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5 linkuse as main transcript	c.43544_43545insT	p.Phe14516IlefsTer8	frameshift_variant	236/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1 linkuse as main transcript	n.502+34669dup		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000128

AC:

AN:

235130

Hom.:

AF XY:

0.00000787

AC XY:

AN XY:

127030

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:

0.0000285

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1453796

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

722266

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000271

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary dilated cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 20, 2015

The p.Phe11948fs variant in TTN has been identified in 1 individual with DCM and VT (LMM unpublished data). This variant is predicted to cause a frameshift, whi ch alters the protein?s amino acid sequence beginning at position 11948 and lead s to a premature termination codon 8 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Frameshift 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.Phe11948fs variant is located in I-band in the highly expressed exon 185. This variant has also been identified in 3/47886 European chromosomes by the Exome Aggregation C onsortium (ExAC, http://exac.broadinstitute.org); however, for diseases with cli nical variability and reduced penetrance, pathogenic variants may be present at a low frequency in the general population. In summary, although additional studi es are required to fully establish its clinical significance, the p.Phe11948fs v ariant is likely pathogenic. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 17, 2022

This sequence change creates a premature translational stop signal (p.Phe14516Ilefs*8) 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 (rs752856716, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 202536). 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 10, 2014

c.38621dupT: p.Phe12875IlefsX8 (F12875IfsX8) in exon 186 of the TTN gene (NM_001256850.1). The normal sequence with the bases that are duplicated in braces is: GCTG{T}ATTT Although the c.38621dupT variant in the TTN gene has not been reported to our knowledge, this mutation causes a shift in reading frame starting at codon Phenylalanine 12875, changing it to an Isoleucine, and creating a premature stop codon at position 8 of the new reading frame, denoted p.Phe12875IlefsX8. This mutation is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. A c.38622dupA mutation (denoted c.38621_38622insA due to a difference in nomenclature), resulting in the same frameshift (denoted p.Ala12873fs), has been reported in a 30-year-old female with DCM and a history of ICD implantation (Herman et al., 2012). However, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles (Herman D et al., 2012). Furthermore, c.38621dupT is not located in the A-band region of titin, where the majority of truncating mutations associated with DCM have been reported (Herman D et al., 2012). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in DCM-CRDM panel(s). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

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