Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000152270 | SCV000201115 | uncertain significance | not specified | 2014-05-01 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Benign. The His17408Tyr var iant in TTN has not been previously reported in individuals with cardiomyopathy or in large population studies. Computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this infor mation is not predictive enough to rule out pathogenicity. It should be noted th at several other species (armadillo, green seaturtle, painted turtle, and 5 fish es) carry a tyrosine (Tyr) at this position, suggesting that this change may be tolerated. This variant is located in the last three bases of the exon, which is part of the 5' splice region. Computational tools do not predict altered splici ng, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the His17408Tyr variant is uncert ain, the presence of this variant in other species suggests that it is more like ly to be benign. |
Gene |
RCV001704100 | SCV000237359 | likely benign | not provided | 2021-03-31 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000474565 | SCV000542908 | uncertain significance | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2016-12-25 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV000618262 | SCV000735257 | likely benign | Cardiovascular phenotype | 2020-03-26 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
Fulgent Genetics, |
RCV000765563 | SCV000896878 | 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 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
ARUP Laboratories, |
RCV000152270 | SCV001160292 | uncertain significance | not specified | 2019-03-01 | criteria provided, single submitter | clinical testing | The c.52222C>T; p.His17408Tyr variant (rs727503588) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall frequency of 0.03 percent in the East Asian population (identified on 6 out of 19,198 chromosomes). This variant is directly 5' to a canonical donor splice site, and though a variant of this adjacent base has been reported in dilated cardiomyopathy, the c.52222C>T has not been reported. This missense variant affects a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical splice site. Without functional mRNA splicing however, the p.His17408Tyr variant cannot be classified with certainty. |
Revvity Omics, |
RCV001704100 | SCV003827307 | uncertain significance | not provided | 2021-01-28 | criteria provided, single submitter | clinical testing | |
New York Genome Center | RCV003227676 | SCV003925300 | uncertain significance | Dilated cardiomyopathy 1G; Hypertrophic cardiomyopathy 9 | 2022-01-28 | criteria provided, single submitter | clinical testing | The c.59926C>T (p.His19976Tyr) missense variant identified in the TTN gene has not been reported in affected individuals in the literature. The variant has 0.00003946 allele frequency in the gnomAD (v3.1.2) database (6 out of 152058 heterozygous alleles, no homozygotes) suggesting it is not a common benign variant in the populations represented in that database. The variant has been reported in the ClinVar database as a variant of uncertain significance (4 entries) and likely benign (2 entries) (Variation ID: 165933). The variant affects a moderately conserved residue (His19976) located in the A-band domain of the TTN gene (PMID: 25589632). The TTN gene has 363 exons (transcript NM_001267550.2), and this variant alters the last nucleotide of exon 302 suggesting that it may affect the normal mRNA splicing. In silico tools provide conflicting predictions about potential pathogenicity of this variant (CADD score = 22.5,REVEL score = 0.082, Splice AI = 0.00, TRAP = 0.551]. Based on the available evidence, the c.59926C>T (p.His19976Tyr) missense variant identified in the TTN gene is reported as a Variant of Uncertain Significance. |
Prevention |
RCV003415993 | SCV004116724 | uncertain significance | TTN-related condition | 2022-10-11 | criteria provided, single submitter | clinical testing | The TTN c.59926C>T variant is predicted to result in the amino acid substitution p.His19976Tyr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.031% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179456705-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |