Submissions for variant NM_001267550.2(TTN):c.835C>T (p.Arg279Trp)

gnomAD frequency: 0.00029  dbSNP: rs138060032

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172493	SCV000051348	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000219791	SCV000272796	likely benign	not specified	2018-04-09	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Labcorp Genetics (formerly Invitae), Labcorp	RCV000468349	SCV000542790	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-05-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000172493	SCV000609012	uncertain significance	not provided	2017-04-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000617531	SCV000735597	uncertain significance	Cardiovascular phenotype	2018-11-13	criteria provided, single submitter	clinical testing	The p.R279W variant (also known as c.835C>T), located in coding exon 5 of the TTN gene, results from a C to T substitution at nucleotide position 835. The arginine at codon 279 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was reported in cis with a truncating TTN alteration in a family with both dilated cardiomyopathy and peripartum cardiomyopathy (van Spaendonck-Zwarts KY et al. Eur Heart J. 2014;35:2165-73). This alteration has also been reported as a secondary cardiac variant in an exome cohort, and was detected in a sudden unexplained death case with variants in other cardiac-related genes (Ng D et al. Circ Cardiovasc Genet. 2013;6:337-46; Sanchez O et al. PLoS ONE. 2016;11(12):e0167358). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769143	SCV000900517	likely benign	Cardiomyopathy	2020-12-10	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000172493	SCV001146514	uncertain significance	not provided	2018-09-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001131435	SCV001291056	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	RCV001134416	SCV001294155	uncertain significance	Tibial muscular dystrophy	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	RCV001134417	SCV001294156	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	RCV001134418	SCV001294157	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.
Illumina Laboratory Services, Illumina	RCV000013495	SCV001294158	uncertain significance	Myopathy, myofibrillar, 9, with early respiratory failure	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Revvity Omics, Revvity	RCV000172493	SCV003824781	uncertain significance	not provided	2022-10-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000219791	SCV004021283	likely benign	not specified	2023-06-19	criteria provided, single submitter	clinical testing	Variant summary: TTN c.835C>T (p.Arg279Trp) results in a non-conservative amino acid change located in the Z-disk region of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 282792 control chromosomes, predominantly at a frequency of 0.00036 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00039), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.835C>T has been reported in the literature in multiple individuals affected with TTN-related conditions without strong evidence for causality (e.g., Lange_2005, Campuzan_2015, Sanchez_2016, van Spaendonck-Zwart_2014). At-least two co-occurrences with other pathogenic variant(s) have been reported in cis with this variant (TTN c.87491C>T, p.Pro29164Leu, Lange_2005; c.69086_69095del10, p.Arg23029ThrfsX9, van Spaendonck-Zwart_2014), providing supporting evidence for a benign role. Two publications report experimental evidence evaluating an impact on protein function, demonstrating reduced binding to nbd1 in mutant cells (Lange_2005, Chaveau_2014). However, neither study provides quantitative data indicating the strength of the effect. The following publications have been ascertained in the context of this evaluation (PMID: 26516846, 24105469, 24569025, 24578547, 27930701, 20708934, 24558114, 15802564, 24271327, 24231549). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Six submitters classified the variant as a variant of uncertain significance, and two classified it as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
OMIM	RCV000013495	SCV000033742	pathogenic	Myopathy, myofibrillar, 9, with early respiratory failure	2005-06-10	no assertion criteria provided	literature only
GeneDx	RCV000172493	SCV000238291	not provided	not provided	2014-09-04	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).
Clinical Genetics, Academic Medical Center	RCV000172493	SCV001925766	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000172493	SCV001956969	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172493	SCV001974406	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000172493	SCV002034949	uncertain significance	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000172493	SCV002036914	uncertain significance	not provided		no assertion criteria provided	clinical testing