NM_001267550.2:c.100026_100030delGTCTT

Variant names:

• chr2-178537078-GAAGAC-G
• rs727503537
• NM_001267550.2:c.100026_100030delGTCTT

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.100026_100030delGTCTT​(p.Ser33344HisfsTer7) 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTN NM_001267550.2 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 10.0
• 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 2-178537078-GAAGAC-G is Pathogenic according to our data. Variant chr2-178537078-GAAGAC-G is described in CliVar as Likely_pathogenic. Clinvar id is 165667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178537078-GAAGAC-G is described in CliVar as Likely_pathogenic. Clinvar id is 165667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178537078-GAAGAC-G is described in CliVar as Likely_pathogenic. Clinvar id is 165667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178537078-GAAGAC-G is described in CliVar as Likely_pathogenic. Clinvar id is 165667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178537078-GAAGAC-G is described in CliVar as Likely_pathogenic. Clinvar id is 165667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178537078-GAAGAC-G is described in CliVar as Likely_pathogenic. Clinvar id is 165667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178537078-GAAGAC-G is described in CliVar as Likely_pathogenic. Clinvar id is 165667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178537078-GAAGAC-G is described in CliVar as Likely_pathogenic. Clinvar id is 165667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178537078-GAAGAC-G is described in CliVar as Likely_pathogenic. Clinvar id is 165667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178537078-GAAGAC-G is described in CliVar as Likely_pathogenic. Clinvar id is 165667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178537078-GAAGAC-G is described in CliVar as Likely_pathogenic. Clinvar id is 165667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178537078-GAAGAC-G is described in CliVar as Likely_pathogenic. Clinvar id is 165667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178537078-GAAGAC-G is described in CliVar as Likely_pathogenic. Clinvar id is 165667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178537078-GAAGAC-G is described in CliVar as Likely_pathogenic. Clinvar id is 165667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178537078-GAAGAC-G is described in CliVar as Likely_pathogenic. Clinvar id is 165667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178537078-GAAGAC-G is described in CliVar as Likely_pathogenic. Clinvar id is 165667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178537078-GAAGAC-G is described in CliVar as Likely_pathogenic. Clinvar id is 165667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178537078-GAAGAC-G is described in CliVar as Likely_pathogenic. Clinvar id is 165667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178537078-GAAGAC-G is described in CliVar as Likely_pathogenic. Clinvar id is 165667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178537078-GAAGAC-G is described in CliVar as Likely_pathogenic. Clinvar id is 165667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.100026_100030delGTCTT	p.Ser33344HisfsTer7	frameshift_variant	Exon 356 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.100026_100030delGTCTT	p.Ser33344HisfsTer7	frameshift_variant	Exon 356 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Nov 30, 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.Ser33344Hisfs*7) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 31112426; internal data). ClinVar contains an entry for this variant (Variation ID: 165667). 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. -

Primary dilated cardiomyopathy Pathogenic:1

Sep 12, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Ser30776fs variant in TTN has not been previously reported in individuals wi th cardiomyopathy. Data from large population studies is insufficient to assess the frequency of this variant. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 30776 and l eads to a premature termination codon 7 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Frameshift and other truncating variants in TTN are strongly associated with DCM, particularly if th ey are located in the exons encoding for the A-band region of the protein (Herma n 2012, Pugh 2014), where this variant is located. In summary, although addition al studies are required to fully establish its clinical significance, the Ser307 76fs variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		10

Splicing

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

Other links and lift over

dbSNP: rs727503537; hg19: chr2-179401805;