Submissions for variant NM_001267550.2(TTN):c.99496G>T (p.Glu33166Ter)

dbSNP: rs886038825

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000250744	SCV000318215	likely pathogenic	Cardiovascular phenotype	2013-01-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000786242	SCV003926241	likely pathogenic	not provided	2022-11-17	criteria provided, single submitter	clinical testing	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; Not observed at significant frequency in large population cohorts (gnomAD); 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); Has not been previously published as pathogenic or benign in association with cardiomyopathy or skeletal myopathy to our knowledge; This variant is associated with the following publications: (PMID: 28152038, 22335739)
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786242	SCV000924985	likely pathogenic	not provided	2016-08-24	no assertion criteria provided	provider interpretation	TTN p.E30598X (c.91792G>T) using transcript NM_133378.4 Please note that this variant has more recently been reported under alternate nomenclature TTN p.E24101X (c.72301G>T) using transcript NM_003319.4. We have seen this variant in a single family, segregating in two affected individuals. Based on the data reviewed below, we consider this variant to be a likely contributor to DCM. The presence of truncating 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). While truncating variants in TTN have been associated with disease, other truncating TTN variants have been reported in approximately 3% of control alleles (Herman D et al. 2012). 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 chr2:179402438C>A. LRG exon number is 356, N2BA transcript is 305. It is located in the A-band, 100% spliced in, in an IgG-like domain. Another variant in the same exon has previously been reported in Herman et al., 2012 in their control population. This nonsense mutation has not previously been reported in the literature. It is not listed in ClinVar. This variant is located in exon 304 of the TTN gene. This alteration results form a G to T substitution at nucleotide position 91792. This changes the amino acid from a glutamate to a stop codon within a highly conserved region of exon 304. There is no variation at at this genomic position listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 8/2016). The mean coverage at that site in ExAC is ~95x with median coverage of 100x More than 95% of individuals have 50x coverage.