Submissions for variant NM_001267550.2(TTN):c.39430G>A (p.Val13144Ile)

gnomAD frequency: 0.00012  dbSNP: rs374394719

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154957	SCV000204639	likely benign	not specified	2014-07-11	criteria provided, single submitter	clinical testing	Val10710Ile in exon 160 of TTN: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, >15 mammals have an isoleucine (Ile) at this position despite high nearby a mino acid conservation. In addition, computational prediction tools do not sugge st a high likelihood of impact to the protein. It has also been identified in 2/ 3748 African American chromosomes by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS/; dbSNP rs374394719).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000531792	SCV000643102	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-06-27	criteria provided, single submitter	clinical testing
GeneDx	RCV001589014	SCV001824603	likely benign	not provided	2019-05-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001589014	SCV002047813	uncertain significance	not provided	2021-07-10	criteria provided, single submitter	clinical testing	The TTN c.39430G>A; p.Val13144Ile variant (rs374394719; ClinVar Variation ID: 178222) is rare in the general population (<0.2% 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.Val13144Ile 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). PMID: 26567375. Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. PMID: 22335739.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149947	SCV003838630	likely benign	Cardiomyopathy	2021-09-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154957	SCV005726951	uncertain significance	not specified	2024-11-08	criteria provided, single submitter	clinical testing	Variant summary: TTN c.32128G>A (p.Val10710Ile) results in a conservative amino acid change located in the I band region of the encoded protein sequence. Three of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.7e-05 in 247996 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Autosomal Recessive Titinopathy, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.32128G>A in individuals affected with Autosomal Recessive Titinopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 178222). Based on the evidence outlined above, the variant was classified as uncertain significance.