Submissions for variant NM_001267550.2(TTN):c.47191C>T (p.Arg15731Cys)

gnomAD frequency: 0.00229  dbSNP: rs72677231

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000040277	SCV000051724	benign	not specified	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040277	SCV000063968	likely benign	not specified	2015-06-16	criteria provided, single submitter	clinical testing	p.Arg13163Cys in exon 201 of TTN: This variant is not expected to have clinical significance because it has been identified in 0.4% (234/66658) of European chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs72650031).
Genetic Services Laboratory, University of Chicago	RCV000040277	SCV000153276	likely benign	not specified	2016-05-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000206445	SCV000237209	benign	not provided	2020-07-16	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27930701, 25163546, 24503780, 23861362, 29961767)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081905	SCV000261583	benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000253777	SCV000317480	likely benign	Cardiovascular phenotype	2013-03-26	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.
Eurofins Ntd Llc (ga)	RCV000040277	SCV000333472	likely benign	not specified	2015-08-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000382285	SCV000423151	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	RCV000291644	SCV000423152	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	RCV000346585	SCV000423153	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	RCV000283374	SCV000423155	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	RCV000343176	SCV000423156	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769010	SCV000900383	benign	Cardiomyopathy	2018-06-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000206445	SCV001152905	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	TTN: PP3, BS1
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040277	SCV001360463	benign	not specified	2019-08-13	criteria provided, single submitter	clinical testing	Variant summary: TTN c.39487C>T (p.Arg13163Cys) results in a non-conservative amino acid change located in the A-band 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 0.0023 in 248102 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 3.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is benign. c.39487C>T has been reported in the literature in sequencing studies of individuals affected with a variety of cardiac phenotypes (example, Pugh_2014). 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Six of these submitters have classified the variant as likely benign (n=5)/benign (n=1). Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000206445	SCV001472532	likely benign	not provided	2023-06-28	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000040277	SCV001474996	benign	not specified	2019-12-31	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000206445	SCV001743282	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000040277	SCV001925073	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000206445	SCV001926611	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000040277	SCV001951314	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000040277	SCV001972279	benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541157	SCV004794384	likely benign	TTN-related disorder	2021-06-02	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).