Submissions for variant NM_001267550.2(TTN):c.19547A>T (p.Lys6516Met)

gnomAD frequency: 0.00025  dbSNP: rs199796249

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172398	SCV000051251	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000172398	SCV000238269	likely benign	not provided	2020-10-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000346409	SCV000424424	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	RCV000401694	SCV000424425	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	RCV000306811	SCV000424426	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	RCV000342923	SCV000424427	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	RCV000303063	SCV000424429	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	RCV000464696	SCV000543076	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-10-05	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000172398	SCV000701413	uncertain significance	not provided	2016-11-29	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000172398	SCV001160407	uncertain significance	not provided	2022-03-17	criteria provided, single submitter	clinical testing	The TTN c.15815A>T; p.Lys5272Met variant (rs199796249; ClinVar Variation ID: 192021) is rare in the general population (<1% 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.Lys5272Met variant cannot be determined with certainty.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170094	SCV001332633	likely benign	Cardiomyopathy	2022-12-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000172398	SCV002541976	uncertain significance	not provided	2021-07-26	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000172398	SCV003826577	uncertain significance	not provided	2023-12-26	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535176	SCV004120007	uncertain significance	TTN-related disorder	2022-11-23	criteria provided, single submitter	clinical testing	The TTN c.19547A>T variant is predicted to result in the amino acid substitution p.Lys6516Met. This variant was reported as a variant of uncertain significance in an unselected exome cohort being analyzed to identify highly penetrant secondary arrhythmia and cardiomyopathy-associated gene variants (described in Supplementary Table 3 as c.15815A>T, p.Lys5272Met based on transcript NM_133378.4 in Ng et al. 2013. PubMed ID: 23861362). This variant is reported in 0.031% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179593004-T-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV000172398	SCV004148118	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	TTN: BP4