Submissions for variant NM_001267550.2(TTN):c.59926C>T (p.His19976Tyr)

gnomAD frequency: 0.00005  dbSNP: rs727503588

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized 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.
GeneDx	RCV001704100	SCV000237359	likely benign	not provided	2021-03-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	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: seen in unaffected individuals, 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, 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, Molecular Genetics and Genomics, 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, Revvity	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.
PreventionGenetics, part of Exact Sciences	RCV004532695	SCV004116724	uncertain significance	TTN-related disorder	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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786406	SCV005399459	uncertain significance	Dilated cardiomyopathy 1G	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. 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. Variants in this gene that result in a premature truncating codon (PTC) are known to have reduced penetrance in DCM (PMID: 25589632). (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to tyrosine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (15 heterozygotes, 0 homozygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated C-terminal A-band and the exon has a PSI score of 100 (PMID: 25589632). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as both a VUS and as likely benign (ClinVar, LOVD, VCGS). (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) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign