Submissions for variant NM_001267550.2(TTN):c.55925T>A (p.Leu18642Gln)

gnomAD frequency: 0.00047  dbSNP: rs140714512

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172658	SCV000051316	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154653	SCV000204329	uncertain significance	not specified	2016-02-09	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Leu16074Gln v ariant in TTN has been identified by our laboratory in 5 Caucasian individuals w ith different cardiomyopathies (1 adult with DCM, 1 adult with DCM and skeletal myopathy, 1 adult with LVNC, 1 teenager with DCM and syndromic features, and 1 i nfant with HCM). This variant has been identified in 50/66574 European chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs140714512). Computational prediction tools and conservation analysis sugg est that the p.Leu16074Gln variant may not impact the protein, though this infor mation is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Leu16074Gln variant is uncertain, its frequency and lack of conservation suggests that it is more likely to be benign.
GeneDx	RCV000172658	SCV000237322	likely benign	not provided	2020-11-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23861362, 24503780)
Ambry Genetics	RCV000251794	SCV000318038	uncertain significance	Cardiovascular phenotype	2013-01-06	criteria provided, single submitter	clinical testing	There is insufficient or conflicting evidence for classification of this alteration.
Eurofins Ntd Llc (ga)	RCV000172658	SCV000332605	uncertain significance	not provided	2015-06-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000299433	SCV000422743	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	RCV000400539	SCV000422745	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.
Illumina Laboratory Services, Illumina	RCV000298398	SCV000422746	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	RCV000360237	SCV000422747	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	RCV000264643	SCV000422748	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085015	SCV000542392	benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2025-01-30	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000356712	SCV000995214	uncertain significance	Hypertrophic cardiomyopathy	2017-06-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000172658	SCV001152864	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	TTN: BP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154653	SCV001338544	uncertain significance	not specified	2020-04-20	criteria provided, single submitter	clinical testing	Variant summary: TTN c.48221T>A (p.Leu16074Gln) results in a non-conservative amino acid change located in the A-band domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00051 in 248080 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Cardiomyopathy (0.00051 vs 0.00063), allowing no conclusion about variant significance. c.48221T>A has been reported in the literature in individuals affected with sudden unexplained death, without strong evidence for causality (Campuzano_2015). These reports 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. Five submitters have classified the variant as VUS while two have classified it as likely benign/benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000172658	SCV002050003	likely benign	not provided	2021-07-23	criteria provided, single submitter	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000172658	SCV001798729	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000154653	SCV001921248	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000172658	SCV001932545	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000172658	SCV001958576	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172658	SCV001967037	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004534960	SCV004744657	likely benign	TTN-related disorder	2019-05-10	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).