ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.77646_77662delinsAGA (p.Ile25883fs) (rs794729345)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000184335 SCV000236960 pathogenic not provided 2019-01-16 criteria provided, single submitter clinical testing Identified in unrelated patients with DCM either referred for genetic testing at GeneDx or in published literature (Herman et al., 2012); Reported in ClinVar as likely pathogenic (ClinVar Variant ID# 202472; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); 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); This variant is associated with the following publications: (PMID: 22335739)
Ambry Genetics RCV000619684 SCV000737207 likely pathogenic Cardiovascular phenotype 2016-12-01 criteria provided, single submitter clinical testing The c.50451_50467del17insAGA variant, located in coding exon 153 of the TTN gene, results from the deletion of 17 nucleotides and insertion of 3 nucleotides, causing a translational frameshift with a predicted alternate stop codon (p.I16818Dfs*3). This alteration is located in the A-band region of the N2-B isoform of the titin protein. Truncating alterations in TTN have been 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 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.

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