rs794729338

chr2-178574145-TCATATGC-TTA

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001267550.2(TTN):c.71980_71986delinsTA(p.Ala23994Ter) variant causes a stop gained, frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTN NM_001267550.2 stop_gained, frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.27

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-178574146-CATATGC-TA is Pathogenic according to our data. Variant chr2-178574146-CATATGC-TA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 202465.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.71980_71986delinsTA	p.Ala23994Ter	stop_gained, frameshift_variant	326/363	ENST00000589042.5
TTN-AS1	NR_038272.1	n.2044-8426_2044-8420delinsTA		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.71980_71986delinsTA	p.Ala23994Ter	stop_gained, frameshift_variant	326/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.417-23450_417-23444delinsTA		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 20, 2023

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: 26315439, 30609409, 22335739) -

Primary dilated cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 22, 2018

The p.Ala21426X (NM_133432.3 c.64276_64282delinsTA) variant in TTN (also reporte d as c.67057_67063delGCATATGinsTA p.Ala22353fs in the literature) has been prev iously reported in 1 heterozygous proband with dilated cardiomyopathy (DCM) and segregated with disease in 10 family members (7 confirmed to have the variant an d 3 obligate carriers) (Herman 2012). This variant has also been reported as pat hogenic in ClinVar (ClinVar#202465; NM_001256850.1: p.Ala22353Terfs), and was ab sent from large population studies, though the ability of these studies to accur ately detect indels may be limited. This variant leads to a premature terminatio n codon at position 21426, which is predicted to lead to a truncated or absent p rotein. Frameshift and other truncating variants in TTN are strongly associated with DCM if they are located in the exons encoding the A-band (Herman 2012, Pugh 2014) and/or are located in an exon that is highly expressed in the heart (Robe rts 2015), both of which are true for this variant. In addition, pathogenic vari ants in TTN, when found on both copies of the gene, are associated with recessiv e centronuclear myopathy. In summary, this variant meets criteria to be classi fied as pathogenic for DCM in an autosomal dominant manner based upon a predicte d null effect and its segregation in affected individuals, as well as likely pat hogenic for centronuclear myopathy in a recessive manner. -

Centronuclear myopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 22, 2018

The p.Ala21426X (NM_133432.3 c.64276_64282delinsTA) variant in TTN (also reporte d as c.67057_67063delGCATATGinsTA p.Ala22353fs in the literature) has been prev iously reported in 1 heterozygous proband with dilated cardiomyopathy (DCM) and segregated with disease in 10 family members (7 confirmed to have the variant an d 3 obligate carriers) (Herman 2012). This variant has also been reported as pat hogenic in ClinVar (ClinVar#202465; NM_001256850.1: p.Ala22353Terfs), and was ab sent from large population studies, though the ability of these studies to accur ately detect indels may be limited. This variant leads to a premature terminatio n codon at position 21426, which is predicted to lead to a truncated or absent p rotein. Frameshift and other truncating variants in TTN are strongly associated with DCM if they are located in the exons encoding the A-band (Herman 2012, Pugh 2014) and/or are located in an exon that is highly expressed in the heart (Robe rts 2015), both of which are true for this variant. In addition, pathogenic vari ants in TTN, when found on both copies of the gene, are associated with recessiv e centronuclear myopathy. In summary, this variant meets criteria to be classi fied as pathogenic for DCM in an autosomal dominant manner based upon a predicte d null effect and its segregation in affected individuals, as well as likely pat hogenic for centronuclear myopathy in a recessive manner. -

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: rs794729338; hg19: chr2-179438873;