chr2-178546391-AT-A

Variant names:

• chr2-178546391-AT-A
• rs1553521978
• NM_001267550.2:c.94939delA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001267550.2(TTN):​c.94939delA​(p.Ile31647LeufsTer10) variant causes a 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 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.93

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 12 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 2-178546391-AT-A is Pathogenic according to our data. Variant chr2-178546391-AT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 534988.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTN	NM_001267550.2	c.94939delA	p.Ile31647LeufsTer10	frameshift_variant	Exon 342 of 363	ENST00000589042.5	NP_001254479.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTN	ENST00000589042.5	c.94939delA	p.Ile31647LeufsTer10	frameshift_variant	Exon 342 of 363	5	NM_001267550.2	ENSP00000467141.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Nov 25, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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 not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the TTN gene (p.Ile31647Leufs*10). It is expected to result in an absent or disrupted protein product. -

not provided Pathogenic:1

Dec 18, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

TTN, Exon 342,p.Ile31647Leufs*10 (c.94939delA) (NM_001267550.2; chr2-179411119-T-) We have seen this variant in a family with DCM. SCICD Classification: likely pathogenic variant based on absence in the general population and type and location of variant. We do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: TTN encodes titin (also known as connectin), the largest protein in humans; titin plays a critical role in the elastic properties of the sarcomere. Two titin molecules span the sarcomere, anchored at the Z-line and M-line. TTN truncating variants are seen in 13-30% of people with DCM and are thought to confer pathogenesis in a dominant-negative fashion (Herman et al 2012, Roberts et al 2015). There is strong evidence implicating them in the pathogenesis of DCM, though it remains unclear whether they are confer risk in a Mendelian or multifactorial fashion (Watkins et al 2015). Furthermore, each individual TTN variant must be evaluated carefully for potential pathogenicity given the presence of truncating TTN variants in 1-3% of the general population (Herman et al 2012, Roberts et al 2015) and the failure of some TTN truncating variants to segregate in DCM families (Norton et al 2013). TTN truncating variants located in the A-band and in exons frequently included in the cardiac isoforms N2B and N2BA are enriched in DCM patients versus controls (Roberts et al 2015). However, it is notable that when focusing these variants (A-band, frequently included N2B, N2BA), 15% of DCM cases and 1% of a normal sample have such variants (Roberts et al 2015). Roberts et al (2015) estimated that when such a variant is found in a proband there is a 93% chance it is disease-causing. The genomic coordinates for this variant are chr2-179411119 (hg19). Per the TTN tool at cardiodb.org, LRG exon number is 342 (this is a meta exon number system created to include all TTN exons and preferred in reporting variants), N2BA transcript is 292. It is located in the A-band, 100% spliced in to cardiac isoforms, in an Ig-like 136 domain. Three other varianst in the same exon has previously been reported in DCM (Roberts et al 2015, Fatkin et al 2016). Case data (not including our patient): none reported Segregation data: none reported Functional data: none reported Population data: The variant is not listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Per Varsome.org, the average coverage at that site in genomes is 34x whereas in exomes it is 89x. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553521978; hg19: chr2-179411118;