Submissions for variant NM_001267550.2(TTN):c.30485C>T (p.Thr10162Met)

gnomAD frequency: 0.00029  dbSNP: rs200593368

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040107	SCV000063798	uncertain significance	not specified	2015-08-03	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000725352	SCV000237057	likely benign	not provided	2021-01-12	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28771489)
Ambry Genetics	RCV000253899	SCV000317818	uncertain significance	Cardiovascular phenotype	2012-11-16	criteria provided, single submitter	clinical testing	There is insufficient or conflicting evidence for classification of this alteration.
Eurofins Ntd Llc (ga)	RCV000725352	SCV000336259	uncertain significance	not provided	2015-10-08	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000262132	SCV000423787	uncertain significance	Dilated cardiomyopathy 1G	2018-01-13	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	RCV000300682	SCV000423788	benign	Tibial muscular dystrophy	2018-01-13	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	RCV000353220	SCV000423789	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2018-01-13	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	RCV000260855	SCV000423790	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2018-01-13	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	RCV000385979	SCV000423792	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J	2018-01-13	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.
Invitae	RCV000475078	SCV000542714	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-12-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000725352	SCV001153005	uncertain significance	not provided	2020-09-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170630	SCV001333221	benign	Cardiomyopathy	2022-03-11	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000725352	SCV003824746	uncertain significance	not provided	2022-08-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040107	SCV003934144	likely benign	not specified	2023-05-03	criteria provided, single submitter	clinical testing	Variant summary: TTN c.26753C>T (p.Thr8918Met) results in a non-conservative amino acid change located in the I-band region of the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00042 in 249288 control chromosomes, predominantly at a frequency of 0.00082 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-fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.26753C>T has been reported in the literature, primarily as a VUS, in settings of multigene panel testing in at least two individuals affected with Dilated Cardiomyopathy, one of whom also had a truncating TTN variant (rs794729258), and in individuals with other cardiomyopathies, all without evidence for causality (e.g. Hertz_2016, Campuzano_2015, Minoche_2019, Fomin_2021). 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 publications have been ascertained in the context of this evaluation (PMID: 26516846, 34731013, 26383259, 35207729, 29961767). Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant either as benign (n=2)/likely benign (n=1), or VUS (n=6). Based on the evidence outlined above, the variant was classified as likely benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000725352	SCV001740773	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000725352	SCV001923475	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000725352	SCV001969083	likely benign	not provided		no assertion criteria provided	clinical testing