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

gnomAD frequency: 0.00001  dbSNP: rs878854324

Total submissions: 4

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	RCV004599211	SCV000742432	pathogenic	Cardiovascular phenotype	2024-06-07	criteria provided, single submitter	clinical testing	The p.R11576* pathogenic mutation (also known as c.34726C>T), located in coding exon 131 of the TTN gene, results from a C to T substitution at nucleotide position 34726. This changes the amino acid from an arginine to a stop codon within coding exon 131. 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This variant (also referred to as p.R20641*, c.61921C>T) has been detected in individuals from dilated cardiomyopathy cohorts (Enriquez A et al. Circ Arrhythm Electrophysiol, 2021 Sep;14:e010006; Zhao Y et al. Signal Transduct Target Ther, 2023 Jun;8:226). 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). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
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 Center for Mendelian Genomics, Broad Institute of MIT and Harvard	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).