Submissions for variant NM_001267550.2(TTN):c.63589A>G (p.Ile21197Val)

gnomAD frequency: 0.00054  dbSNP: rs72646855

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000082417	SCV000054964	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040467	SCV000064158	uncertain significance	not specified	2015-04-04	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Ile18629Val v ariant in TTN has been previously identified by our laboratory in 1 Caucasian ad ult with cardiomyopathy, ventricular tachycardia and atrial fibrillation. This v ariant has also been identified in 0.1% (18/16250) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s72646855). Isoleucine (Ile) at position 18629 is not conserved in mammals or ev olutionarily distant species. Of note, Xenopus tropicalis and 9 different fish s pecies carry a valine (Val) at this position, raising the possibility that this change may be tolerated. Additional computational prediction tools support that the p.Ile18629Val variant may not impact the protein. In summary, while the clin ical significance of the p.Ile18629Val variant is uncertain, its frequency and p resence in other species suggests that it is more likely to be benign.
Eurofins Ntd Llc (ga)	RCV000082417	SCV000114416	uncertain significance	not provided	2017-12-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000082417	SCV000237405	likely benign	not provided	2021-02-18	criteria provided, single submitter	clinical testing
Invitae	RCV001086280	SCV000286774	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000393151	SCV000422390	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.
Illumina Laboratory Services, Illumina	RCV000297845	SCV000422391	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	RCV000357132	SCV000422392	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	RCV000262231	SCV000422393	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	RCV000312697	SCV000422394	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.
Athena Diagnostics Inc	RCV000040467	SCV000616123	likely benign	not specified	2019-09-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000619500	SCV000736912	likely benign	Cardiovascular phenotype	2019-10-04	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852825	SCV000995554	likely benign	Cardiomyopathy	2018-05-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000082417	SCV001152817	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	TTN: BP4
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000082417	SCV003800221	uncertain significance	not provided	2023-08-31	criteria provided, single submitter	clinical testing	The TTN c.63589A>G; p.Ile21197Val variant (rs72646855; ClinVar Variation ID: 47197) 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.Ile21197Val 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	RCV000040467	SCV003934119	benign	not specified	2023-05-08	criteria provided, single submitter	clinical testing	Variant summary: TTN c.55885A>G (p.Ile18629Val) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00058 in 247742 control chromosomes. The observed variant frequency is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.55885A>G in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign n=1, likely benign n=5, VUS n=4). Based on the evidence outlined above, the variant was classified as benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000082417	SCV004225840	uncertain significance	not provided	2023-02-09	criteria provided, single submitter	clinical testing	BP4
Blueprint Genetics	RCV000143969	SCV000188850	likely benign	Primary familial hypertrophic cardiomyopathy	2013-12-20	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000040467	SCV001925720	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000082417	SCV001932701	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000082417	SCV001952544	likely benign	not provided		no assertion criteria provided	clinical testing