rs794729367

chr2-178535516-TC-TAG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001267550.2(TTN):c.101098delinsCT(p.Asp33700LeufsTer13) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D33700D) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TTN NM_001267550.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.91

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

Verdict is Pathogenic. Variant got 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 2-178535517-C-AG is Pathogenic according to our data. Variant chr2-178535517-C-AG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 202498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.101098delinsCT	p.Asp33700LeufsTer13	frameshift_variant	358/363	ENST00000589042.5
TTN-AS1	NR_038272.1	n.220-215delinsAG		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.101098delinsCT	p.Asp33700LeufsTer13	frameshift_variant	358/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.416+11881delinsAG		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2023

This sequence change creates a premature translational stop signal (p.Asp33700Leufs*13) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individual(s) with clinical features of dilated cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 223390). This variant is located in the M band of TTN (PMID: 25589632). Truncating variants in this region have been previously reported in individuals affected with autosomal recessive myopathy and muscular dystrophy (PMID: 18948003, 23975875, 24395473). 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). 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

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 30, 2014

c.96175delinsCT: p.Asp32059LeufsX13 (D32059LfsX13) in exon 308 of the TTN gene (NM_001256850.1). The normal sequence with the bases that are deleted in braces andinserted in brackets is: TAGT{G}[CT]ATGT. Although the c.96175delGinsCT mutation in the TTN gene has not been reported to our knowledge, this mutation causes a shift in reading frame starting at codon Aspartic acid 32059, changing it to a Leucine, and creating a premature stop codon at position 13 of the new reading frame, denoted p.Asp32059LeufsX13. 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. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman D et al., 2012). However, c.96175delGinsCT is 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). In summary, c.96175delGinsCT in the TTN gene is interpreted as a disease-causing mutation. The variant is found in DCM,DCM-CRDM panel(s). -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2016

The c.73903delGinsCT variant, located in coding exon 185 of the TTN gene, results from the deletion of one nucleotide and insertion of two nucleotides, causing a translational frameshift with a predicted alternate stop codon (p.D24635Lfs*13). This variant is located in the M-band region of the N2-B isoform of the titin protein. This variant has not been reported in the literature to date; however, a similar frameshift alteration involving the same codon, p.D24635Vfs*13 (reported as c.101098_101099insT (p.Asp33700fs)), has been described in an individual with dilated cardiomyopathy (DCM) (Roberts AM et al. Sci Transl Med. 2015;7(270):270ra6). This c.73903delGinsCT variant was previously reported in the SNPDatabase as rs794729367, but was absent from population-based cohorts in the NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project databases. In the ESP, this variant was not observed in 6264 samples (12528 alleles) with coverage at this position. Truncating alterations in TTN have been observed at a significantly higher frequency among patients with DCM, or 54/203 (27%), compared to patients with hypertrophic cardiomyopathy (3 of 231, 1%, P=3x10-16) and healthy controls (7 of 249, 3%, P=9x10-14). Among families with multiple relatives with DCM, studies also provided strong data demonstrating segregation of TTN truncations with disease (Herman DS et al. N Engl J Med. 2012;366(7):619-28; Pugh TJ et al. Genet Med. 2014;16(8):601-8). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of TTN has not been clearly established as a mechanism of disease. As such, this variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs794729367; hg19: chr2-179400244;