rs768431507

chr2-178605011-G-A

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.54166C>T(p.Arg18056Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000125 in 1,600,382 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TTN NM_001267550.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 4.61

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 2-178605011-G-A is Pathogenic according to our data. Variant chr2-178605011-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 202509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178605011-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.54166C>T	p.Arg18056Ter	stop_gained	280/363	ENST00000589042.5
TTN-AS1	NR_038272.1	n.4198G>A		non_coding_transcript_exon_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.54166C>T	p.Arg18056Ter	stop_gained	280/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.502+7330G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151878 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000833 AC: 2 AN: 240104 Hom.: 0 AF XY: 0.00000769 AC XY: 1 AN XY: 129966

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448504 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 719082

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: 9.06e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151878 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74160

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000351 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

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

Jul 07, 2023

This variant is also known as p.R9183X, R15488*. 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. 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). ClinVar contains an entry for this variant (Variation ID: 202509). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 25163546, 27813223, 29650543, 33874732). This variant is present in population databases (rs768431507, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Arg18056*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. -

Dilated cardiomyopathy 1G Pathogenic:1

Pathogenic, no assertion criteria provided

research

deCODE genetics, Amgen

Jul 21, 2023

The variant NM_001267550.2:c.54166C>T (chr2:178605011) in TTN was detected in 6 heterozygotes out of 58K WGS Icelanders (MAF= 0,005%). This variant has been reported in ClinVar previously as pathogenic/likely pathogenic. Based on ACMG criteria (PVS1, PM2, PP5) this variant classifies as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 14, 2023

Identified in patients with cardiomyopathy in published literature and in patients referred for genetic testing at GeneDx (Haas et al., 2015; Jansweijer et al., 2017; Jansen et al., 2019; van Lint et al., 2019; Goli et al., 2021; Vissing et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Located in the A-band region of TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (Herman et al., 2012); This variant is associated with the following publications: (PMID: 29650543, 22335739, 33106378, 25163546, 27813223, 33874732, 31112426, 30847666) -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2022

The p.R8991* variant (also known as c.26971C>T), located in coding exon 107 of the TTN gene, results from a C to T substitution at nucleotide position 26971. This changes the amino acid from an arginine to a stop codon within coding exon 107. 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%). This alteration, noted as p.R9183* (c.27547C>T), has been reported in a dilated cardiomyopathy (DCM) cohort (Haas J et al. Eur Heart J, 2015 May;36:1123-35a). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. While truncating variants in TTN are present in 1-3% of the general population, truncating variants in the A-band are the most common cause of dilated cardiomyopathy (DCM) (Herman DS et al. N. Engl. J. Med., 2012 Feb;366:619-28; Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6). TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM regardless of their position in titin (Schafer S et al. Nat. Genet., 2017 01;49:46-53). As such, this alteration is classified as likely pathogenic. -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Mar 26, 2014

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg16415Ter (R16415X): c.49243 C>T in exon 230 of the TTN gene (NM_001256850.1) The variant has been not been previously reported in the literature or clinvar and has not been previously seen in out patient population at Stanford. Truncating TTN variants have been shown by Herman et al. (2012) to be present in 27% of patients with familial dilated cardiomyopathy (DCM) versus approximately 1% of patients with hypertrophic cardiomyopathy (HCM) and were found in 3% of controls. Herman et al. observed strong cosegregation (lod score, 9.3) of nonsense and frameshift variants with clinical status among 60 members of 16 families affected by DCM, indicating an odds of approximately 1 in 10^9 that the segregation of these TTN variants occurred by chance. However, the presence of truncating TTN variants in controls indicates that not all such variants can be presumed to be pathogenic. Norton et al. (2013, Ray Hershberger’s group) found that not all TTN truncating variants segregate with disease. Herman et al. reported that TTN truncating mutations found in subjects with dilated cardiomyopathy (versus those found in subjects without the disease) were nonrandomly distributed within titin: they were overrepresented in the A-band region. Our patient’s variant is also located in the A-band region. In total the variant has not been seen in ~6000 individuals from population datasets. It is not listed in the NHLBI Exome Sequencing Project (ESP) dataset (as of 12/2/2014), which currently includes variant calls on ~4000 Caucasian and ~2000 African American individuals. None of these individuals are ancestry-matched to our patient, whose ancestry is Filipino. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. It is not present in 1000 Genomes (as of 12/2/2014). Our recommendation based on our additional review is that all first degree family members continue to have regular clinical screening as outlined below. We also recommend that any affected family members be tested for this variant to help give us more information about whether this variant segregates with disease in the family. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.63
Cadd	Pathogenic	59
Dann	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	A;A;A;A;A;A
Vest4		0.88
GERP RS		5.0

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: rs768431507; hg19: chr2-179469738; COSMIC: COSV100605290; COSMIC: COSV100605290;