Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV005236515 | SCV001748769 | likely pathogenic | Primary familial dilated cardiomyopathy | 2025-01-16 | criteria provided, single submitter | clinical testing | Variant summary: TTN c.31484-1418_31484-1389del30 (also known as NM_001267550:c.36267_36280+16del30) is located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. Loss of function variants in all TTN bands are strongly associated with a spectrum of autosomal recessive titinopathies when exon expression (proportion spliced in, PSI, 1=complete expression) in skeletal muscle is >0.1 (PMID: 36977548, 39198997, 29598826, 32778822, 29691892, 33449170, 36977548, internal data). In contrast, loss of function variants in all TTN bands are only strongly associated with autosomal dominant TTN-related cardiomyopathies if located in exons constitutively expressed (PSI >0.9) in cardiac muscle, excluding extreme C-terminal exons 359-363 (PMID: 25589632, 31216868, 32964742, 34662387, 27869827, Shetty et al., Nat Cardiovasc Res 2024, cardiodb.org, internal data). This variant has a maximum skeletal muscle PSI of 0.626 and a maximum cardiac muscle PSI of 0.020. The variant allele was found at a frequency of 8.4e-05 in 225022 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (8.4e-05 vs 0.00039), allowing no conclusion about variant significance. c.31484-1418_31484-1389del30 has been reported in the heterozygous state in the literature in individuals affected with TTN-related cardiac conditions, as well as controls (Choi_2020, Jurgens_2022). These report(s) do not provide unequivocal conclusions about association of the variant with TTN-related conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31691645, 35177841). ClinVar contains an entry for this variant (Variation ID: 809022). Based on the evidence outline above, the variant has been classified as Likely Pathogenic for autosomal recessive TTN-related conditions. |
| 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 | |
| Labcorp Genetics |
RCV002549973 | SCV003339705 | likely pathogenic | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2025-01-23 | 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, 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, 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. |