Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000505739 | SCV000236848 | pathogenic | not provided | 2023-04-12 | criteria provided, single submitter | clinical testing | 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; Not observed at significant frequency in large population cohorts (gnomAD); 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); This variant is associated with the following publications: (PMID: Komissarova2022[casereport], 34008412, 32880476, 31931689, 22335739, 29540472) |
Labcorp Genetics |
RCV000800689 | SCV000940419 | pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2023-02-21 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg16766*) 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 (rs754866489, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy (PMID: 29540472; Invitae). ClinVar contains an entry for this variant (Variation ID: 202379). 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 | RCV002444748 | SCV002734920 | pathogenic | Cardiovascular phenotype | 2024-09-26 | criteria provided, single submitter | clinical testing | The p.R7701* pathogenic mutation (also known as c.23101C>T), located in coding exon 94 of the TTN gene, results from a C to T substitution at nucleotide position 23101. This changes the amino acid from an arginine to a stop codon within coding exon 94. 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 was reported in individuals with features consistent with dilated cardiomyopathy (DCM) (Hazebroek MR et al. Circ Heart Fail, 2018 03;11:e004682; Ambry internal data). 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 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. |
Laboratory for Molecular Medicine, |
RCV004017467 | SCV004847614 | likely pathogenic | Primary dilated cardiomyopathy | 2019-02-22 | criteria provided, single submitter | clinical testing | The p.Arg14198X variant in TTN has been reported in 1 individual with DCM (Hazebroek 2018) and has been identified in 1/111844 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). It has been reported in ClinVar (Variation ID #202379). This nonsense variant leads to a premature termination codon at position 14198, which is predicted to lead to a truncated or absent protein. Nonsense and other truncating variants in TTN are strongly associated with DCM if they impact the exons encoding for the A-band (Herman 2012, Pugh 2014) and/or are located in an exon that is highly expressed in the heart (Roberts 2015). The p.Arg14198X variant is located in the A-band. In addition, TTN variants have also been associated with myopathies and other neuromuscular conditions, which usually have autosomal recessive inheritance (Savarese 2016). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for TTN-associated diseases. ACMG/AMP Criteria applied: PVS1, PM2. |
Victorian Clinical Genetics Services, |
RCV004786505 | SCV005398544 | pathogenic | Dilated cardiomyopathy 1G | 2022-09-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is known mechanism of disease in this gene. In addition, dominant-negative is also a suggested mechanism (PMID: 25589632). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Protein truncating variants in this gene are known to have reduced penetrance in DCM (PMID: 25589632). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (1 heterozygote, 0 homozygotes). (SP) 0600 - Variant is located in the annotated C-terminal A-band and the exon has a PSI score of 100 (PMID: 25589632). (I) 0703 - Other NMD-predicted variants comparable to the one identified in this case have moderate previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been classified as likely pathogenic, pathogenic or VUS by clinical diagnostic laboratories, and has been identified in at least seven individuals with DCM and five with other cardiac conditions (VCGS; Invitae personal communication; GeneDx personal communication; PMIDs: 29540472, 31216868, 34008412, 31931689). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited (by segregation testing). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |