Submissions for variant NM_001267550.2(TTN):c.17224C>T (p.Leu5742Phe)

gnomAD frequency: 0.00039  dbSNP: rs72648943

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039895	SCV000063586	uncertain significance	not specified	2015-08-12	criteria provided, single submitter	clinical testing	The p.Leu4498Phe variant in TTN has been identified by our laboratory in 2 indiv iduals with HCM. This variant been identified in 30/65610 European American chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs72648943). Computational prediction tools and conservation analysis d o not provide strong support for or against an impact to the protein. In summary , the clinical significance of the p.Leu4498Phe variant is uncertain.
GeneDx	RCV000725312	SCV000238238	likely benign	not provided	2020-12-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28045975, 23396983)
Invitae	RCV000205655	SCV000261430	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-12-08	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000725312	SCV000335953	uncertain significance	not provided	2015-10-13	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852907	SCV000995647	likely benign	Hypertrophic cardiomyopathy	2018-08-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001130952	SCV001290547	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV001133898	SCV001293612	benign	Tibial muscular dystrophy	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV001133899	SCV001293613	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001133900	SCV001293614	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001133901	SCV001293615	uncertain significance	Dilated cardiomyopathy 1G	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000725312	SCV001473977	uncertain significance	not provided	2020-03-09	criteria provided, single submitter	clinical testing	The TTN c.17224C>T; p.Leu5742Phe variant (rs72648943; ClinVar Variation ID: 46625) is reported in the literature in several individuals affected with HCM or DCM, though it was not demonstrated to cause disease (Franaszczyk 2017, Lopes 2013). This variant has been observed together with TTN variants p.Glu33301Lys and p.Val34563Ala in the literature (Franaszczyk 2017, Lopes 2013) and in another individual tested at ARUP Laboratories. This suggests these three variants may occur in cis, although parental testing would be required to confirm this. This variant is rare in the population (<1% allele frequency in the Genome Aggregation Database) and 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.Leu5742Phe 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). Franaszczyk M et al. Titin Truncating Variants in Dilated Cardiomyopathy - Prevalence and Genotype-Phenotype Correlations. PLoS One. 2017 Jan 3;12(1):e0169007. Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. Lopes LR et al. Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. J Med Genet. 2013 Apr;50(4):228-39. Linke WA and Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798130	SCV002042380	benign	Cardiomyopathy	2022-08-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039895	SCV002598994	likely benign	not specified	2022-09-06	criteria provided, single submitter	clinical testing	Variant summary: TTN c.13492C>T (p.Leu4498Phe) results in a non-conservative amino acid change located in the I-band region of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 247170 control chromosomes, predominantly at a frequency of 0.00052 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.13492C>T has been reported in the literature in individuals affected with Dilated Cardiomyopathy and Hypertrophic Cardiomyopathy (Lopes_2013, Franaszczyk_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and five ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Revvity Omics, Revvity	RCV000725312	SCV003826664	uncertain significance	not provided	2021-10-27	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003914965	SCV004742908	uncertain significance	TTN-related condition	2024-01-12	criteria provided, single submitter	clinical testing	The TTN c.17224C>T variant is predicted to result in the amino acid substitution p.Leu5742Phe. This variant has been reported in an individual with hypertrophic or dilated cardiomyopathy (referred to as p.L4498F in Table S1, Lopes et al. 2013. PubMed ID: 23396983; Table S4, Franaszczyk et al. 2017. PubMed ID: 28045975). This variant is reported in 0.057% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.