Submissions for variant NM_001267550.2(TTN):c.66391A>G (p.Thr22131Ala)

gnomAD frequency: 0.00046  dbSNP: rs140842479

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040504	SCV000064195	uncertain significance	not specified	2015-01-14	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Thr19563Ala v ariant in TTN has been identified by our laboratory in 1 adult with DCM, 1 adole scent with DCM, and 1 adolescent with LVNC. This variant has also been identifie d in 0.1% (16/9802) of African chromosomes by the Exome Aggregation Consortium ( ExAC, http://exac.broadinstitute.org; dbSNP rs140842479). Threonine (Thr) at po sition 19563 is not conserved in mammals or evolutionary distant species and add itional computational prediction tools do not provide strong evidence for or aga inst an impact to the protein. In summary, while the clinical significance of th e p.Thr19563Ala variant is uncertain, its frequency suggests that it is more lik ely to be benign.
Fulgent Genetics, Fulgent Genetics	RCV000765558	SCV000896873	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
Invitae	RCV001088816	SCV001006079	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-12	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000184735	SCV001476357	likely benign	not provided	2019-09-26	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000184735	SCV002049546	uncertain significance	not provided	2021-07-10	criteria provided, single submitter	clinical testing	The TTN c.66391A>G; p.Thr22131Ala variant (rs140842479; ClinVar Variation ID: 47234) 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.Thr22131Ala 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040504	SCV002571883	uncertain significance	not specified	2022-08-08	criteria provided, single submitter	clinical testing	Variant summary: TTN c.58687A>G (p.Thr19563Ala) results in a non-conservative amino acid change located in the A-band region, Fibronectin type-III domain of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 279888 control chromosomes (gnomAD), predominantly at a frequency of 0.0014 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.58687A>G has been reported in the literature in one individual affected with Dilated Cardiomyopathy without strong evidence for causality as the patient carried several other TTN variants of uncertain significance (Pugh_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: three classified the variant as of uncertain significance and two as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Ambry Genetics	RCV002321531	SCV002626286	likely benign	Cardiovascular phenotype	2018-09-21	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.
Revvity Omics, Revvity	RCV000184735	SCV003822208	uncertain significance	not provided	2020-07-20	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000184735	SCV004225829	uncertain significance	not provided	2023-01-12	criteria provided, single submitter	clinical testing	BP4
GeneDx	RCV000184735	SCV000237439	not provided	not provided	2014-07-08	no assertion provided	clinical testing	Missense variants in the TTN gene are considered 'unclassified' if they are not previously reported in the literature and do not have >1% frequency in the population to be considered a polymorphism. Research indicates that truncating mutations in the TTN gene are expected to account for approximately 25% of familial and 18% of sporadic idiopathic DCM; however, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles. There has been little investigation into non-truncating variants. (Herman D et al. Truncations of titin causing dilated cardiomyopathy. N Eng J Med 366:619-628, 2012) The variant is found in CARDIOMYOPATHY panel(s).