rs397517576

Positions:

• chr2-178629360-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001267550.2(TTN):​c.44364del​(p.Tyr14789ThrfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,760 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TTN NM_001267550.2 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 0.0600

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 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 2-178629360-AG-A is Pathogenic according to our data. Variant chr2-178629360-AG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46976.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1}. Variant chr2-178629360-AG-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.44364del	p.Tyr14789ThrfsTer15	frameshift_variant	240/363	ENST00000589042.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.44364del	p.Tyr14789ThrfsTer15	frameshift_variant	240/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.502+31681del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460760 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726680

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary dilated cardiomyopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Nov 05, 2023	This sequence change in TTN is a frameshift variant predicted to cause a premature stop codon, p.(Tyr14789Thrfs*15), in constitutively expressed exon 240 (percentage splice in, PSI, 100%) in the I-band (proximal to the A-band). High PSI truncating variants in TTN have a significant association with dilated cardiomyopathy (PMID: 31216868). This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been reported in at least two probands with dilated cardiomyopathy (PMID: 31983221, 36277766). The variant has been reported to segregate with TTN-related myopathy with a second TTN variant in a single family (ClinVar: SCV003922164.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1_Strong, PM2_Supporting, PP1, PS4_Supporting. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	The Tyr12221fs variant (TTN) has not been previous reported, but has been identi fied in one individual with DCM tested by our laboratory. This variant is predic ted to cause a frameshift, which alters the protein's amino acid sequence beginn ing at codon 12221 and leads to a premature stop codon 15 amino acids downstream . This alteration is then predicted to lead to a truncated or absent protein (lo ss of function). Loss-of-function variants in TTN are common in patients with DC M (Herman 2012). In summary, this variant is likely to be pathogenic. -

Early-onset myopathy with fatal cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

May 02, 2023

The heterozygous p.Tyr14789ThrfsTer15 variant in TTN was identified by our study, in the compound heterozygous state with a variant of uncertain significance (ClinVar Variation ID: 284443), in two siblings with Salih myopathy. Familial exome analysis revealed that this variant was in trans with a variant of uncertain significance (ClinVar Variation ID: 284443). The p.Tyr14789ThrfsTer15 variant in TTN has not been previously reported in individuals with Salih myopathy. This variant was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 46976) and has been interpreted with conflicting interpretations of pathogenicity. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 14789 and leads to a premature termination codon 15 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the TTN gene is an established disease mechanism in autosomal recessive Salih myopathy. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for Salih myopathy. ACMG/AMP Criteria applied: PVS1, PM2_Supporting (Richards 2015). -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 13, 2021

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. This variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 25163546). ClinVar contains an entry for this variant (Variation ID: 46976). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr14789Thrfs*15) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs397517576; hg19: chr2-179494087;