Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000480710 | SCV000568553 | pathogenic | not provided | 2024-03-26 | 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; Located in the A-band region of TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (PMID: 22335739); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22335739, 32880476, 26084686, 31112426, 37461109, 24558114) |
Blueprint Genetics | RCV000480710 | SCV000928109 | pathogenic | not provided | 2018-12-11 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV001390945 | SCV001592849 | pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2023-08-31 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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). ClinVar contains an entry for this variant (Variation ID: 420065). This variant is also known as c.82117C>T (p.Arg27373*). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 24558114, 26084686). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Arg29014*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. |
Clinical Genetics Laboratory, |
RCV001731710 | SCV001984987 | pathogenic | Dilated cardiomyopathy 1G | 2020-12-09 | criteria provided, single submitter | clinical testing | PS4, PP1, PP3, PVS1 |
Ambry Genetics | RCV002356779 | SCV002657097 | pathogenic | Cardiovascular phenotype | 2022-06-08 | criteria provided, single submitter | clinical testing | The p.R19949* pathogenic mutation (also known as c.59845C>T), located in coding exon 154 of the TTN gene, results from a C to T substitution at nucleotide position 59845. This changes the amino acid from an arginine to a stop codon within coding exon 154. 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 has been reported in individuals with dilated cardiomyopathy (DCM), including segregating with disease in one family (van Spaendonck-Zwarts KY et al. Eur Heart J, 2014 Aug;35:2165-73; Akinrinade O et al. Eur Heart J, 2015 Sep;36:2327-37). In addition, 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. |
Diagnostic Laboratory, |
RCV000480710 | SCV001742333 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Genome Diagnostics Laboratory, |
RCV000480710 | SCV001932589 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000480710 | SCV001954806 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000480710 | SCV001973801 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Cardiogenetics and Myogenetics Molecular and Cellular Functional Unit, |
RCV001731710 | SCV005375038 | likely pathogenic | Dilated cardiomyopathy 1G | 2024-01-06 | no assertion criteria provided | clinical testing |