Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001532953 | SCV001748769 | uncertain significance | not specified | 2021-06-24 | criteria provided, single submitter | clinical testing | Variant summary: TTN c.31484-1418_31484-1389del30 is located at a position not widely known to affect splicing. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant does not impact a constitutively expressed exon on any of the TTN transcripts as represented by a very low PSI (percentage spliced in) score derived from RNAseq data as represented in the TTN Variants in Dilated Cardiomyopathy database (https://www.cardiodb.org/titin/titin_transcripts.php). The variant allele was found at a frequency of 8.2e-05 in 256400 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (8.2e-05 vs 0.00039), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.31484-1418_31484-1389del30 in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. The LOVD database (https://databases.lovd.nl/shared/variants/0000512416#00001778) classifies this variant as likely benign without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Fulgent Genetics, |
RCV002505517 | SCV002815248 | uncertain significance | 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 | 2021-10-16 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV002549973 | SCV003339705 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2024-01-22 | criteria provided, single submitter | clinical testing | This variant results in the deletion of part of exon 168 (c.36267_36280+16del) of the TTN gene. It is expected to disrupt RNA splicing and likely results in a truncated or disrupted TTN protein. This variant is present in population databases (rs745871962, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 809022). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875, Invitae internal data). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742, Invitae internal data). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| New York Genome Center | RCV003227885 | SCV003925349 | uncertain significance | Dilated cardiomyopathy 1G; Hypertrophic cardiomyopathy 9 | 2022-04-08 | criteria provided, single submitter | clinical testing | The c.36267_36280+16del variant is a 30 base-pair (bps) deletion in the TTN gene which removes the last 14 nucleotides of exon 168 (of 363) and the first 16 nucleotides of the adjacent intron 168 (of 362) of the inferred complete meta-transcript. The deleted region includes the canonical splice-site of exon/intron 168 and is expected to alter the normal mRNA splicing of this inferred meta-transcript. However, this exon 168 of the inferred meta-transcript is not constitutively expressed in any of the TTN transcripts as indicated by a very low PSI (percentage spliced in) score which is an estimate of the percentage of TTN transcripts that incorporate agiven exon (https://www.cardiodb.org/titin/titin_transcripts.php). The c.36267_36280+16del variant has not been reported in affected individuals in the literature. The variant has 0.00009204 allele frequency in the gnomAD (v3.1.2) database (14 out of 152104 heterozygous alleles, no homozygotes) suggesting it is not a common benign variant in the populations represented in that database. This variant is reported as a variant of uncertain significance in the ClinVar database (Variation ID:809022). Based on the available evidence, the c.36267_36280+16del variant identified in the TTN gene is reported as a variant of uncertain significance. |