rs1553547657

Positions:

• chr2-178555037-C-T

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.88422G>A​(p.Trp29474Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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]

(HGNC:):

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 2-178555037-C-T is Pathogenic according to our data. Variant chr2-178555037-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 518944.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.88422G>A	p.Trp29474Ter	stop_gained	331/363	ENST00000589042.5
TTN-AS1	NR_038272.1	n.2043+12676C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.88422G>A	p.Trp29474Ter	stop_gained	331/363	5	NM_001267550.2	P1
	ENST00000624360.1	n.477C>T		non_coding_transcript_exon_variant	1/1
TTN-AS1	ENST00000659121.1	n.416+31401C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 22, 2017

This variant has not been reported in the literature in individuals with TTN-related disease. This sequence change results in a premature translational stop signal in the TTN gene (p.Trp29474*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 6,518 amino acids of the TTN protein. This variant is not present in population databases (ExAC no frequency). This variant is found in the A-band of this gene. While this particular variant has not been reported in the literature, truncating variants in the A-band of TTN are significantly overrepresented in patients with dilated cardiomyopathy and are considered to be likely pathogenic for the disease (PMID: 25589632). A different variant (c.88421G>A) giving rise to the same protein effect observed here (p.Trp29474*) has been reported in individuals with dilated cardiomyopathy (PMID: 26084686), indicating that this residue may be critical for protein function. For these reasons, this variant has been classified as Likely Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2016

The p.W20409* variant (also known as c.61227G>A), located in coding exon 158 of the TTN gene, results from a G to A substitution at nucleotide position 61227. This changes the amino acid from a tryptophan to a stop codon within coding exon 158, and is located in the A-band region of the N2-B isoform of the titin protein. An alteration of an adjacent nucleotide (c.61226G>A), also resulting in p.W20409*, has been previously detected in a dilated cardiomyopathy (DCM) cohort and was reported to segregate with disease in one family (Akinrinade O et al. Eur Heart J. 2015;36(34):2327-37 (reported as c.88421G>A p.Trp29474* due to alternate transcript nomenclature)). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6005 samples (12010 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

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	67
DANN	Benign	0.96
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A;A;A;A
Vest4		0.87
GERP RS		5.7

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: rs1553547657; hg19: chr2-179419764;