rs878854378

Variant names:

• chr2-178533656-ATTG-A
• rs878854378
• NM_001267550.2:c.102956_102958delCAA

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The NM_001267550.2(TTN):​c.102956_102958delCAA​(p.Thr34319del) variant causes a disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTN NM_001267550.2 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.34
• 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001267550.2. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 2-178533656-ATTG-A is Pathogenic according to our data. Variant chr2-178533656-ATTG-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 242429. Variant chr2-178533656-ATTG-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 242429. Variant chr2-178533656-ATTG-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 242429. Variant chr2-178533656-ATTG-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 242429. Variant chr2-178533656-ATTG-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 242429. Variant chr2-178533656-ATTG-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 242429. Variant chr2-178533656-ATTG-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 242429. Variant chr2-178533656-ATTG-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 242429. Variant chr2-178533656-ATTG-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 242429. Variant chr2-178533656-ATTG-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 242429. Variant chr2-178533656-ATTG-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 242429. Variant chr2-178533656-ATTG-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 242429. Variant chr2-178533656-ATTG-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 242429. Variant chr2-178533656-ATTG-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 242429. Variant chr2-178533656-ATTG-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 242429. Variant chr2-178533656-ATTG-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 242429. Variant chr2-178533656-ATTG-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 242429. Variant chr2-178533656-ATTG-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 242429. Variant chr2-178533656-ATTG-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 242429. Variant chr2-178533656-ATTG-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 242429.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.102956_102958delCAA	p.Thr34319del	disruptive_inframe_deletion	Exon 358 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.102956_102958delCAA	p.Thr34319del	disruptive_inframe_deletion	Exon 358 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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Dec 05, 2018

Undiagnosed Diseases Network, NIH

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous c.55018C>T (p.R18340X) pathogenic variant in the TTN gene was detected in this individual. A heterozygous c.95252_95254delCAA (p.T31751del) likely pathogenic variant in the TTN gene was also detected. A heterozygous c.74698A>C (p.K24900Q) variant was also detected and found to be likely benign. The c.55018C>T (p.R18340X) variant is in trans configuration with the c.95252_95254delCAA (p.T31751del) and c.74698A>C (p.K24900Q) variants. -

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

Dec 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.102956_102958del, results in the deletion of 1 amino acid(s) of the TTN protein (p.Thr34319del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 27854218). ClinVar contains an entry for this variant (Variation ID: 242429). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant is located in the M band of TTN (PMID: 25589632). Non-truncating variants in this region may be relevant for neuromuscular disorders, but have not been definitively shown to cause cardiomyopathy (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
PhyloP100		5.3
Mutation Taster		=56/44	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs878854378; hg19: chr2-179398383;