ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.92631dup (p.Lys30878fs) (rs886039145)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000243451 SCV000320326 likely pathogenic Cardiovascular phenotype 2016-08-17 criteria provided, single submitter clinical testing The c.65436dupG variant, located in coding exon 166 of the TTN gene, results from a duplication of G at nucleotide position 65436, causing a translational frameshift with a predicted alternate stop codon (p.K21813Efs*8). This alteration is located in the A-band region of the N2-B isoform of the titin protein. Truncating alterations in TTN were observed at a significantly higher frequency among patients with dilated cardiomyopathy (DCM), or 54/203 (27%), compared to patients with hypertrophic cardiomyopathy (3 of 231, 1%, P=3x10<sup>-16</sup>) and healthy controls (7 of 249, 3%, P=9x10<sup>-14</sup>). Among families with multiple relatives with DCM, studies also provided strong data demonstrating segregation of TTN truncations with disease (Herman DS et al. N Engl J Med. 2012;366(7):619-28; Pugh TJ et al. Genet Med. 2014;16(8):601-8). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6167 samples (12334 alleles) with coverage at this position. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of TTN has not been clearly established as a mechanism of disease. As such, this variant is classified as likely pathogenic.
GeneDx RCV000486705 SCV000566282 pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing Although the c.87708dupG pathogenic variant in the TTN gene has not been reported to ourknowledge, this variant causes a shift in reading frame starting at codon Lysine 29237, changing it to aGlutamic acid, and creating a premature stop codon at position 8 of the new reading frame, denotedp.Lys29237GlufsX8. This pathogenic variant is expected to result in either an abnormal, truncatedprotein product or loss of protein from this allele through nonsense-mediated mRNA decay. Althoughtruncating TTN variants have been reported in approximately 3% of control alleles (Herman et al.,2012), the c.87708dupG variant is located in the A-band region of titin, where the majority oftruncating pathogenic variants associated with DCM have been reported (Herman et al., 2012). Finally,the c.87708dupG variant has not been observed in large population cohorts (Lek et al., 2016; 1000Genomes Consortium et al., 2015; Exome Variant Server).
Invitae RCV000642706 SCV000764393 likely pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2019-04-09 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Lys30878Glufs*8). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 5114 amino acids of the TTN protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TTN-related disease. ClinVar contains an entry for this variant (Variation ID: 264404). This variant is found in the A-band of this gene. Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy (PMID: 25589632). Truncating variants in TTN 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.
GenomeConnect, ClinGen RCV000509249 SCV000606885 not provided TTN-Related disorder no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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