Submissions for variant NM_001267550.2(TTN):c.76115dup (p.Asn25372fs)

dbSNP: rs774604740

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000209488	SCV000189787	likely pathogenic	Primary dilated cardiomyopathy	2014-10-08	criteria provided, single submitter	research	This TTN truncating variant (TTNtv) was identified in two individuals in this cohort and is located in an exon that is highly expressed in the heart. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart.
Invitae	RCV000469186	SCV000542936	likely pathogenic	Dilated cardiomyopathy 1G	2016-08-30	criteria provided, single submitter	clinical testing	This sequence change inserts 1 nucleotide in exon 326 of the TTN mRNA (c.76115dupA), causing a frameshift at codon 25372. This creates a premature translational stop signal (p.Asn25372Lysfs*5) and is expected to result in an absent or disrupted protein product. This variant is found in the A-band of this gene. This particular variant was reported in an individual with dilated cardiomyopathy (PMID: 25589632). 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). ClinVar contains an entry for this variant (Variation ID: 223383). For these reasons, this variant has been classified as Likely Pathogenic.
GeneDx	RCV000483913	SCV000567335	pathogenic	not provided	2021-03-01	criteria provided, single submitter	clinical testing	Identified in patients with DCM referred for genetic testing at GeneDx and in the literature (Roberts et al., 2015; Marston et al., 2015; Vikhorev et al., 2017); also denoted as c.76115dupA (p.Asn25372fs), p.N16499Kfs*5, and c.68408_68411del(A)4ins(A)5 (p.N22804K fs*5) due to the use of alternate transcripts and/or nomenclature; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Frameshift 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 titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012); This variant is associated with the following publications: (PMID: 29093449, 25589632, 26406308)
Illumina Laboratory Services, Illumina	RCV000779287	SCV000915869	uncertain significance	TTN-Related Disorders	2017-08-16	criteria provided, single submitter	clinical testing	The TTN c.68411dupA (p.Asn22804LysfsTer5) variant results in a frameshift, and is predicted to result in premature termination of the protein. This variant has been reported in one study and is found in a heterozygous state in two individuals with dilated cardiomyopathy (Roberts et al. 2015). This variant has not been described in the literature in association with hereditary myopathy with early respiratory failure, hypertrophic cardiomyopathy, recessive limb-girdle muscular dystrophy, Salih myopathy, or Udd distal myopathy. The p.Asn22804LysfsTer5 was absent from 308 controls. The variant is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database but this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. Due to the limited evidence and potential impact of frameshift variants, the p.Asn22804LysfsTer5 variant is classified as a variant of unknown significance but suspicious for pathogenicity for TTN-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV001378109	SCV001575605	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-01-28	criteria provided, single submitter	clinical testing	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: 223383). This variant is also known as p.N23731Kfs*5. This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 25589632, 26406308, 29093449, 34587765). This variant is present in population databases (rs774604740, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Asn25372Lysfs*5) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486769	SCV004240112	pathogenic	Cardiomyopathy	2022-11-08	criteria provided, single submitter	clinical testing