Submissions for variant NM_001267550.2(TTN):c.57442A>G (p.Met19148Val)

gnomAD frequency: 0.00042  dbSNP: rs188185141

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172302	SCV000051296	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000172302	SCV000237331	likely benign	not provided	2021-04-27	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000213728	SCV000272700	uncertain significance	not specified	2017-10-10	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233875	SCV000286735	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-12-14	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000172302	SCV000333162	uncertain significance	not provided	2017-09-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000172302	SCV000575278	uncertain significance	not provided	2016-11-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764323	SCV000895342	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
Illumina Laboratory Services, Illumina	RCV001130772	SCV001290362	benign	Tibial muscular dystrophy	2017-07-18	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001130773	SCV001290363	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001130774	SCV001290364	uncertain significance	Dilated cardiomyopathy 1G	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001130775	SCV001290365	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2017-07-18	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001130776	SCV001290366	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798613	SCV002042549	likely benign	Cardiomyopathy	2020-01-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002433752	SCV002753407	likely benign	Cardiovascular phenotype	2020-05-06	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	RCV000172302	SCV003823598	uncertain significance	not provided	2022-04-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000213728	SCV003934090	likely benign	not specified	2023-05-15	criteria provided, single submitter	clinical testing	Variant summary: TTN c.49738A>G (p.Met16580Val) results in a conservative amino acid change located in the A-band region of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0005 in 248042 control chromosomes, predominantly at a frequency of 0.0009 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. c.49738A>G has been reported in the literature in individuals affected with Dilated Cardiomyopathy without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 35207729). Multiple 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=3) and VUS (n=7). Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000172302	SCV004564126	uncertain significance	not provided	2023-08-24	criteria provided, single submitter	clinical testing	The TTN c.57442A>G; p.Met19148Val variant (rs188185141; ClinVar Variation ID: 191935) is rare in the general population (<0.2% allele frequency in the Genome Aggregation Database) and has been reported in individuals with hypertrophic cardiomyopathy and arrhythmogenic cardiomyopathy (Lopes 2013, Mates 2018). 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.Met19148Val variant cannot be determined with certainty. References: Lopes LR et al. Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. J Med Genet. 2013 Apr;50(4):228-39. PMID: 23396983. Mates J et al. Role of copy number variants in sudden cardiac death and related diseases: genetic analysis and translation into clinical practice. Eur J Hum Genet. 2018 Jul;26(7):1014-1025. PMID: 29511324. 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. Linke WA and Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068. PMID: 24625729.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000172302	SCV001741653	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000172302	SCV001920904	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000172302	SCV001928627	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000213728	SCV001959466	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172302	SCV001970022	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000172302	SCV002035904	likely benign	not provided		no assertion criteria provided	clinical testing