Submissions for variant NM_001267550.2(TTN):c.71602C>T (p.Arg23868Ter)

dbSNP: rs397517689

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000208052	SCV000064262	pathogenic	Primary dilated cardiomyopathy	2019-07-16	criteria provided, single submitter	clinical testing	The p.Arg21300X variant in TTN has been identified by our laboratory in 2 adults with DCM. In one family, it segregated with disease in 7 affected relatives (including 3 obligate carriers). This variant has also been identified in 0.001% (1/112282) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID: 47301). This nonsense variant leads to a premature termination codon at position 21300, which is predicted to lead to a truncated or absent protein. Nonsense and other truncating variants in TTN are strongly associated with DCM, particularly if they are located in the exons encoding for the A-band region of the protein (Herman 2012, Pugh 2014), where this variant is located. In summary, this variant meets criteria to be classified as pathogenic for DCM in an autosomal dominant manner based on segregation studies and the predicted effect of this variant on the protein. ACMG/AMP Criteria applied: PVS1; PP1_Strong; PM2.
GeneDx	RCV000184258	SCV000236880	pathogenic	not provided	2021-11-23	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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; 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: 28798025, 22335739, 24503780, 28416588, 23975875, 25589632, 26735901, 29447731, 31514951, 33874732)
Blueprint Genetics	RCV000208052	SCV000264283	likely pathogenic	Primary dilated cardiomyopathy	2015-07-01	criteria provided, single submitter	clinical testing
Invitae	RCV000542963	SCV000642461	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg23868*) 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 present in population databases (rs397517689, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy and/or peripartum cardiomyopathy (PMID: 26735901, 28416588; Invitae). This variant is also known as chr2:179439257G>A and c.44407C>T (p.Arg14803*). ClinVar contains an entry for this variant (Variation ID: 47301). 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000623243	SCV000740484	pathogenic	Primary familial dilated cardiomyopathy	2017-02-16	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768934	SCV000900307	pathogenic	Cardiomyopathy	2022-04-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000184258	SCV001502354	likely pathogenic	not provided	2020-10-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002326756	SCV002632294	pathogenic	Cardiovascular phenotype	2022-12-29	criteria provided, single submitter	clinical testing	The p.R14803* pathogenic mutation (also known as c.44407C>T), located in coding exon 153 of the TTN gene, results from a C to T substitution at nucleotide position 44407. This changes the amino acid from an arginine to a stop codon within coding exon 153. 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 (also referred to as p.R23868* and p.R14995*) has been identified in individuals from peripartum cardiomyopathy, dilated cardiomyopathy, and noncompaction cardiomyopathy cohorts (Ware JS et al. N. Engl. J. Med., 2016 Jan;374:233-41; Dal Ferro M et al. Heart, 2017 11;103:1704-1710; Miszalski-Jamka K et al. Circ Cardiovasc Genet. 2017 Aug;10(4); van Waning JI et al. J Am Coll Cardiol. 2018 Feb;71(7):711-722; Jansen M et al. Circ Genom Precis Med. 2019 May;12(5):e002436). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV002490565	SCV002809558	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	2021-11-06	criteria provided, single submitter	clinical testing
3billion	RCV003152675	SCV003841347	pathogenic	Dilated cardiomyopathy 1G	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000047301 / PMID: 26735901). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
New York Genome Center	RCV003448251	SCV004176219	pathogenic	Dilated cardiomyopathy 1G; Hypertrophic cardiomyopathy 9	2023-08-03	criteria provided, single submitter	clinical testing	The c.71602C>T p.(Arg23868Ter) stop-gain variant identified in the TTN gene has been previously reported in individuals with titinopathies [PMID: 31514951, 26735901, 28416588, 29447731], and has been deposited in ClinVar as Pathogenic/Likely Pathogenic by multiple laboratories [ClinVar ID: 47301]. The c.71602C>T variant is present as a single heterozygous allele in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.71602C>T variant is located in exon 326 (A band) of this 363-exon gene, is predicted to incorporate a premature translation termination codon [p.(Arg23868Ter)], and is expected to result in loss-of-function through protein truncation or nonsense mediated mRNA decay. Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy [PMID: 25589632]. Based on available evidence, this c.71602C>T p.(Arg23868Ter) variant identified in TTN is classified as Pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000184258	SCV001742881	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000184258	SCV001932597	pathogenic	not provided		no assertion criteria provided	clinical testing
deCODE genetics, Amgen	RCV003152675	SCV004022129	pathogenic	Dilated cardiomyopathy 1G	2023-07-21	no assertion criteria provided	research	The variant NM_001267550.2:c.71602C>T (chr2:178574530) in TTN was detected in 3 heterozygotes out of 58K WGS Icelanders (MAF= 0,003%). This variant has been reported in ClinVar previously as pathogenic/likely pathogenic. Based on ACMG criteria (PVS1, PM2, PP5) this variant classifies as pathogenic.