ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.68308del (p.Thr22770fs)

dbSNP: rs1064796112
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480170 SCV000572543 pathogenic not provided 2023-06-08 criteria provided, single submitter clinical testing 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 TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (Herman et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22335739)
Invitae RCV000798881 SCV000938520 pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2023-09-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr22770Leufs*29) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of limb-girdle muscular dystrophy (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 422942). 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). For these reasons, this variant has been classified as Pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV001653859 SCV001870369 pathogenic Dilated cardiomyopathy 1G 2021-06-24 criteria provided, single submitter research ACMG codes:PVS1, PM2, PP5
Ambry Genetics RCV002323839 SCV002628030 likely pathogenic Cardiovascular phenotype 2022-11-30 criteria provided, single submitter clinical testing The c.41113delA variant, located in coding exon 148 of the TTN gene, results from a deletion of one nucleotide at nucleotide position 41113, causing a translational frameshift with a predicted alternate stop codon (p.T13705Lfs*29). 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 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.
Fulgent Genetics, Fulgent Genetics RCV002481527 SCV002785535 likely pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9 2021-07-24 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000480170 SCV004226730 pathogenic not provided 2022-05-13 criteria provided, single submitter clinical testing PM1, PM2_supporting, PVS1

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