Submissions for variant NM_001267550.2(TTN):c.66039del (p.Ser22014fs)

dbSNP: rs1553628052

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000549200	SCV000642453	likely pathogenic	Dilated cardiomyopathy 1G	2017-05-02	criteria provided, single submitter	clinical testing	This sequence change deletes 1 nucleotide from exon 314 of the TTN mRNA (c.66039delC), causing a frameshift at codon 22014. This creates a premature translational stop signal (p.Ser22014Alafs*8) 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	RCV001379950	SCV001577862	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-05-01	criteria provided, single submitter	clinical testing	This sequence change deletes 1 nucleotide from exon 314 of the TTN mRNA (c.66039delC), causing a frameshift at codon 22014. This creates a premature translational stop signal (p.Ser22014Alafs*8) 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786248	SCV000924994	likely pathogenic	not provided	2017-05-09	no assertion criteria provided	provider interpretation	Given that this is a truncating variant in the A-band, we consider this variant likely disease-causing and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant has not been reported before in the literature. Truncating variants in the A-band region of TTN are overrepresented in individuals with dilated cardiomyopathy versus the general population (Herman et al 2012). Truncating variants in the A band of titin have not previously been associated with lone atrial fibrillation. However, we have a cohort here that suggests that these types of variants can predispose individuals to an arrhythmic cardiomyopathy. However, the presence of trunctating TTN variants in controls indicates that not all such variants can be presumed pathogenic. 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 variants have been shown by Herman et al. (2012) to be present in 27% of patients with familial dilated cardiomyopathy (DCM) versus approximately 1% of patients with hypertrophic cardiomyopathy (HCM) and 3% of controls (indicating that not all such variants are disease-causing). In addition, Norton et al. (2013) showed that not all truncating variants in TTN segregate with disease (DCM) in affected families—pointing to the difficulty in determining variant pathogenicity for a specific truncating variant. Norton et al., identified 6 TTN truncating variants carried by individuals affected with DCM in 7 of 17 DCM families (logarithm of odds, 2.99); 2 of these 7 families also had novel missense variants that segregated with disease. Two additional novel truncating TTN variants did not segregate with DCM. Roberts et al, 2015 performed cardiac phenotyping of 5267 affected and unaffected individuals as well as TTN DNA sequencing and RNA and protein analyses heart tissue. They have a resource at cardiodb.org/titin that lists the relative inclusion of TTN exons in different isoforms and provides information to guide assessment of pathogenicity of specific truncation variants in the gene. Variants located in the A-band and present in cardiac isoforms of the protein were enriched in DCM patients versus controls. The genomic coordinates for this variant are chr2:179447144. LRG exon number is 314, N2BA transcript is 264. It is located in the A-band, 100% spliced in, in a fibronectin type III domain. Another variant in the same exon has previously been reported in Roberts et al. 2015 in their cardiomyopathy population. This 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. The average coverage at that site in gnomAD is 57.6x.