Submissions for variant NM_001267550.2(TTN):c.36044C>G (p.Thr12015Arg)

dbSNP: rs199868380

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172357	SCV000055021	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226876	SCV000286601	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-12-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000172357	SCV001472652	uncertain significance	not provided	2020-06-02	criteria provided, single submitter	clinical testing	The TTN c.36044C>G; p.Thr12015Arg variant (rs199868380; ClinVar Variation ID: 191988) is rare in the general population (<1% allele frequency in the Genome Aggregation Database) and has not been reported in the medical literature in association with dilated cardiomyopathy (DCM) or other TTN-related disease. The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Thus, the clinical significance of the p.Thr12015Arg variant cannot be determined with certainty. References: Begay RL et al. Role of Titin Missense Variants in Dilated Cardiomyopathy. J Am Heart Assoc. 2015 Nov 13;4(11). Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. Linke WA and Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068.
CeGaT Center for Human Genetics Tuebingen	RCV000172357	SCV004183824	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	TTN: BP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479043	SCV004223399	likely benign	not specified	2025-01-30	criteria provided, single submitter	clinical testing	Variant summary: TTN c.31484-1871C>G is located at a position not widely known to affect splicing. This variant corresponds to c.36044C>G (p.Thr12015Arg) in NM_001267550. Several computational tools predict a significant impact on normal splicing: Two predict the variant strengthens a cryptic 3' acceptor site. One predicts the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00036 in 1597802 control chromosomes, predominantly at a frequency of 0.00045 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.15 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039).The variant (described as c.36044C>G (p.Thr12015Arg)) has been reported in the literature in individuals affected with cardiac disease phenotypes (e.g. Andersen_2019, Pham_2023), including at least one patient affected with Dilated Cardiomyopathy (DCM), however this patient also carried another likely pathogenic TTN variant, which could explain the phenotype (Pham_2023). These reports 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: 31392414, 37199186). ClinVar contains an entry for this variant (Variation ID: 191988). Based on the evidence outlined above, the variant was classified as likely benign.