Submissions for variant NM_001267550.2(TTN):c.97114dup (p.Arg32372fs)

dbSNP: rs1064793419

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486249	SCV000566076	likely pathogenic	not provided	2022-01-31	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); 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); Reported in ClinVar as a likely pathogenic variant (ClinVar Variant ID# 418768); This variant is associated with the following publications: (PMID: 22335739)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000559029	SCV000642485	likely pathogenic	Dilated cardiomyopathy 1G	2017-02-24	criteria provided, single submitter	clinical testing	This sequence change inserts 1 nucleotide in exon 348 of the TTN mRNA (c.97114dupA), causing a frameshift at codon 32372. This creates a premature translational stop signal (p.Arg32372Lysfs*9) and is expected to result in a disrupted protein product. 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). For these reasons, this variant has been classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001379068	SCV001576797	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg32372Lysfs*9) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 418768). 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). 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.
PreventionGenetics, part of Exact Sciences	RCV004722816	SCV005337463	likely pathogenic	TTN-related disorder	2024-09-11	no assertion criteria provided	clinical testing	The TTN c.97114dupA variant is predicted to result in a frameshift and premature protein termination (p.Arg32372Lysfs*9). This variant occurs within the A-band region of the titin protein in which truncating TTN variants have been found more frequently in dilated cardiomyopathy patients than in controls (Herman DS et al. 2012. PubMed ID: 22335739). RNAseq studies from heart tissue indicate this exon is commonly included in TTN mRNA transcripts (PSI of 100%, Roberts AM et al. 2015. PubMed ID: 25589632; https://cardiodb.org/titin/titin_transcripts.php). TTN truncating variants are reported in 1-2% of presumably healthy individuals and occur more frequently in exons with low PSI values, indicating that this variant is more likely to be disease causing (Herman et al. 2012. PMID: 22335739; Roberts et al. 2015. PMID: 25589632). To our knowledge, this variant has not been reported in the literature or a large population database , indicating this variant is rare. Of note, truncating TTN variants in constitutive exons (PSI > 90%) are significantly associated with dilated cardiomyopathy (DCM) irrespective of their position in TTN (Schafer S et al. 2017. PubMed ID: 27869827). In addition, truncating TTN variants have been associated with autosomal recessive congenital titinopathies (Oates et al. 2018. PubMed ID: 29691892; Bryen et al. 2020. PubMed ID: 31660661). Therefore, the c.97114dupA variant is interpreted as likely pathogenic for recessive and dominant TTN-related disorders.