Submissions for variant NM_001267550.2(TTN):c.91715dup (p.Asn30572fs)

dbSNP: rs779129892

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	RCV000209618	SCV000189760	uncertain significance	Primary dilated cardiomyopathy	2014-10-08	criteria provided, single submitter	research	This TTN truncating variant (TTNtv) was identified in one individual 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000663410	SCV000786698	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J		criteria provided, single submitter	research	The heterozygous p.Asn30572fs variant in TTN has been identified in the compound heterozygous state by our project in one individual with Limb Girdle Muscular Dystrophy. This variant has not been reported in the literature but compound heterozygous loss of function variants have been previously described in individuals with Limb Girdle Muscular Dystrophy (source: ClinVar). This variant has been entered in ClinVar in one unaffected person in DCM study (Variation ID 223353) and has been identified in 0.01% (1/15280) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs779129892). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain.
Blueprint Genetics	RCV000788446	SCV000927561	likely pathogenic	not provided	2018-03-02	criteria provided, single submitter	clinical testing
Invitae	RCV001379493	SCV001577305	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn30572Lysfs*16) 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 present in population databases (rs779129892, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with TTN-related conditions (PMID: 32528171, 33106378). ClinVar contains an entry for this variant (Variation ID: 223353). 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.
Ambry Genetics	RCV002363047	SCV002656551	likely pathogenic	Cardiovascular phenotype	2021-12-10	criteria provided, single submitter	clinical testing	The c.64520dupA variant, located in coding exon 164 of the TTN gene, results from a duplication of A at nucleotide position 64520, causing a translational frameshift with a predicted alternate stop codon (p.N21507Kfs*16). 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 variant (also referred to as c.91715_91716insA and c.91715dup) has been detected in a population-based cohort study and in a cohort with limb-girdle muscle weakness and/or elevated creatine kinase; however, clinical details were limited (Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6; Töpf A et al. Genet Med, 2020 09;22:1478-1488). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Center for Human Genetics, University of Leuven	RCV000209618	SCV002817406	likely pathogenic	Primary dilated cardiomyopathy	2022-12-31	criteria provided, single submitter	clinical testing