Submissions for variant NM_001267550.2(TTN):c.30718G>T (p.Val10240Phe)

gnomAD frequency: 0.00153  dbSNP: rs111671438

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172682	SCV000051432	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040111	SCV000063802	uncertain significance	not specified	2014-03-13	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Val8996Phe vari ant in TTN has now been reported by our laboratory in two Caucasian adults with cardiomyopathy: one with family history of LVNC and sudden death, who carried a pathogenic variant in another gene, and one with family history of DCM and sudde n death. This variant has also been identified in 0.2% (14/7946) European Americ an chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.e du; dbSNP rs111671438). While this frequency suggests that this variant is more likely benign, it is too low to confidently rule out a disease causing role. Com putational prediction tools and conservation analyses do not provide strong supp ort for or against an impact to the protein. Additional information is needed to fully assess its clinical significance.
GeneDx	RCV000040111	SCV000237060	likely benign	not specified	2017-09-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Eurofins Ntd Llc (ga)	RCV000172682	SCV000333469	uncertain significance	not provided	2015-07-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084360	SCV000555391	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-26	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000040111	SCV000597701	uncertain significance	not specified	2016-08-09	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000040111	SCV000616052	benign	not specified	2019-12-26	criteria provided, single submitter	clinical testing
Phosphorus, Inc.	RCV000578117	SCV000679957	uncertain significance	Dilated cardiomyopathy 1G	2017-08-01	criteria provided, single submitter	clinical testing
Phosphorus, Inc.	RCV000577956	SCV000679958	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-08-01	criteria provided, single submitter	clinical testing
Phosphorus, Inc.	RCV000578036	SCV000679959	uncertain significance	Tibial muscular dystrophy	2017-08-01	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852879	SCV000995613	likely benign	Cardiomyopathy; Long QT syndrome; Hypertrophic cardiomyopathy	2018-04-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000172682	SCV001153002	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	TTN: BP4
Illumina Laboratory Services, Illumina	RCV000578036	SCV001288946	benign	Tibial muscular dystrophy	2018-01-12	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	RCV000578117	SCV001288947	uncertain significance	Dilated cardiomyopathy 1G	2018-01-12	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	RCV001129423	SCV001288948	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2018-01-12	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	RCV000577956	SCV001288949	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J	2018-01-12	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	RCV001129424	SCV001288950	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2018-01-12	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040111	SCV001360730	likely benign	not specified	2019-12-24	criteria provided, single submitter	clinical testing	Variant summary: TTN c.26986G>T (p.Val8996Phe) results in a non-conservative amino acid change located in the I-band region of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00084 in 151082 control chromosomes, predominantly at a frequency of 0.0018 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 2.9-fold the estimated maximal allele frequency expected for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.26986G>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating an impact on protein function have been reported in the literature. Co-occurrence with another pathogenic variant has been reported (MYH7 c.1207C>T, p.Arg403Trp-internal sample), providing supporting evidence for a benign role. Seven ClinVar submitters (evaluation after 2014) have cited the variant as likely benign (n=4) and uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000172682	SCV001473161	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing	The TTN c.30718G>T; p.Val10240Phe variant (rs111671438; ClinVar Variation ID: 46841) 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.Val10240Phe 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000172682	SCV001744850	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000172682	SCV001800194	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000040111	SCV001919159	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172682	SCV001974655	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541143	SCV004760940	likely benign	TTN-related disorder	2022-02-01	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).