ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.61921C>T (p.Arg20641Ter)

gnomAD frequency: 0.00001  dbSNP: rs878854324
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000229380 SCV000286765 pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2024-01-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg20641*) 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 individuals with dilated cardiomyopathy (PMID: 29540472, 34315225; Invitae). ClinVar contains an entry for this variant (Variation ID: 238819). 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.
Ambry Genetics RCV000623841 SCV000742432 likely pathogenic Inborn genetic diseases 2017-04-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: NEGATIVE - No Relevant Alterations Detected (Step 2)
GeneDx RCV001589176 SCV001822565 pathogenic not provided 2022-03-27 criteria provided, single submitter clinical testing Reported in a patient with dilated cardiomyopathy, however, additional detailed clinical information and segregation analysis were not provided (Haebroek et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); Located in the A-band region of the TTN gene, where the majority of truncating pathogenic variants associated with dilated cardiomyopathy have been reported (Herman et al., 2012); 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; This variant is associated with the following publications: (PMID: 25589632, 11717165, 23518707, 23418287, 1745277, 24395473, 22335739, 12145747, 18948003, 21810661, 17444505, 24105469, 32880476, 34315225, 29540472)
Broad Institute Rare Disease Group, Broad Institute RCV003225936 SCV003922163 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2J 2023-05-02 criteria provided, single submitter curation The heterozygous p.Arg20641Ter variant in TTN was identified by our study, in the compound heterozygous state with a variant of uncertain significance (ClinVar Variation ID: 1304094), in one individual with limb girdle muscular dystrophy. Trio exome analysis revealed that this variant was in trans with a variant of uncertain significance (ClinVar Variation ID: 1304094). The p.Arg20641Ter variant in TTN has not been previously reported in individuals with limb girdle muscular dystrophy 10 but has been identified in 0.002% (1/41434) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs878854324). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 238819) and has been interpreted as pathogenic by GeneDx and as likely pathogenic by Ambry and Invitae. This nonsense variant leads to a premature termination codon at position 20641, which is predicted to lead to a truncated or absent protein. Loss of function of the TTN gene is an established disease mechanism in autosomal recessive limb girdle muscular dystrophy 10. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for limb girdle muscular dystrophy 10. ACMG/AMP Criteria applied: PVS1, PM2_Supporting (Richards 2015).

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