Submissions for variant NM_001267550.2(TTN):c.57586C>G (p.Leu19196Val)

gnomAD frequency: 0.00006  dbSNP: rs397517630

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040396	SCV000064087	uncertain significance	not specified	2014-02-04	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Leu16628Val var iant in TTN has been identified by our laboratory in one individual with HCM and one individual with desminopathy, both of whom carried a likely pathogenic vari ant in another gene. This variant was not identified in large population studie s. Computational analyses (biochemical amino acid properties, conservation, Alig nGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impa ct to the protein. In summary, additional information is needed to fully assess the clinical significance of the Leu166278Val variant.
Genetic Services Laboratory, University of Chicago	RCV000118768	SCV000153308	uncertain significance	not provided	2014-03-31	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000118768	SCV000228180	uncertain significance	not provided	2016-06-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000118768	SCV000237333	likely benign	not provided	2021-01-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000253459	SCV000318399	uncertain significance	Cardiovascular phenotype	2013-03-11	criteria provided, single submitter	clinical testing	There is insufficient or conflicting evidence for classification of this alteration.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000467434	SCV000542541	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-07-20	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852835	SCV000995565	likely benign	Ventricular tachycardia	2019-03-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001135095	SCV001294865	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	RCV001135096	SCV001294866	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	RCV001135097	SCV001294867	likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV001135098	SCV001294868	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	RCV001135099	SCV001294869	likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Baylor Genetics	RCV001135096	SCV001521142	uncertain significance	Dilated cardiomyopathy 1G	2020-07-28	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798164	SCV002042550	likely benign	Cardiomyopathy	2020-01-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040396	SCV002511948	likely benign	not specified	2022-04-25	criteria provided, single submitter	clinical testing	Variant summary: TTN c.49882C>G (p.Leu16628Val) results in a conservative amino acid change located in the A-band of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 271140 control chromosomes, predominantly at a frequency of 0.00038 within the Latino subpopulation in the gnomAD database. This frequency is slightly lower than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00038 vs 0.00039), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.49882C>G in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign n=4, VUS n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Revvity Omics, Revvity	RCV000118768	SCV003821047	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing