rs727505076

Positions:

• chr2-178551187-ACGC-ATCACACCCACTTA

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.91341_91343delinsTAAGTGGGTGTGA​(p.Leu30447PhefsTer5) variant causes a stop gained, frameshift change. 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: 33)
• Consequence: TTN NM_001267550.2 stop_gained, frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.70

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 2-178551188-CGC-TCACACCCACTTA is Pathogenic according to our data. Variant chr2-178551188-CGC-TCACACCCACTTA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTN	NM_001267550.2	c.91341_91343delinsTAAGTGGGTGTGA	p.Leu30447PhefsTer5	stop_gained, frameshift_variant	336/363	ENST00000589042.5	NP_001254479.2
TTN-AS1	NR_038272.1	n.2043+8827_2043+8829delinsTCACACCCACTTA		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.91341_91343delinsTAAGTGGGTGTGA	p.Leu30447PhefsTer5	stop_gained, frameshift_variant	336/363	5	NM_001267550.2	ENSP00000467141	P1
TTN-AS1	ENST00000659121.1	n.416+27552_416+27554delinsTCACACCCACTTA		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

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

Apr 16, 2014

The Leu27879fs variant in TTN has not been identified in individuals with cardio myopathy or in large population studies. This frameshift variant is predicted to alter the protein's amino acid sequence beginning at position 27879 and lead to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Nonsense and other truncati ng variants in TTN are strongly associated with DCM and the majority occur in th e A-band (Herman 2012, Pugh 2014), where this variant is located. In summary, th is variant is likely pathogenic, though additional studies are required to fully establish its clinical significance. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2024

The c.64146_64148delGCGinsTAAGTGGGTGTGA (p.L21382Ffs*5) alteration, located in exon 164 (coding exon 163) of the TTN gene, consists of an deletion of 3 and insertion of 13 nucleotides causing a translational frameshift at position 64146 with a predicted alternate stop codon after 5 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This exon is located in the A-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). Based on the available evidence, this alteration 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: rs727505076; hg19: chr2-179415915;