Submissions for variant NM_001267550.2(TTN):c.19016A>G (p.Tyr6339Cys)

gnomAD frequency: 0.00022  dbSNP: rs192553687

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154987	SCV000204669	uncertain significance	not specified	2014-03-24	criteria provided, single submitter	clinical testing	The Tyr5095Cys variant in TTN has not been reported in individuals with cardiomy opathy, but has been identified in 3/8186 chromosomes by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS/) and in 1.0% (2/194) of Han Chine se chromosomes by the 1000 Genomes Project (dbSNP rs192553687). Computational pr ediction tools and conservation analysis suggest that this variant may not impac t the protein, though this information is not predictive enough to rule out path ogenicity. Additional information is needed to fully assess the clinical signifi cance of this variant.
Eurofins Ntd Llc (ga)	RCV000724663	SCV000231881	uncertain significance	not provided	2016-09-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000724663	SCV000238262	likely benign	not provided	2019-03-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27066507)
Invitae	RCV000232825	SCV000286480	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2018-01-09	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001129645	SCV001289185	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001129646	SCV001289186	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001129647	SCV001289187	uncertain significance	Dilated cardiomyopathy 1G	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001132363	SCV001292022	benign	Tibial muscular dystrophy	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001132364	SCV001292023	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154987	SCV001362587	uncertain significance	not specified	2019-08-12	criteria provided, single submitter	clinical testing	Variant summary: TTN c.15284A>G (p.Tyr5095Cys) results in a non-conservative amino acid change located in the Immunoglobulin V-set domain (IPR013106) of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 246820 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Cardiomyopathy (0.00012 vs 0.00063), allowing no conclusion about variant significance. c.15284A>G has been reported in the literature in at-least one individual affected with ARVC (Ceyhan-Birsoy_2015). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrences with other another likely pathogenic variant has been reported (PKP2 Exon 8 del in the patient with ARVC mentioned above), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000724663	SCV001714658	uncertain significance	not provided	2020-08-05	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000724663	SCV002770596	uncertain significance	not provided	2022-02-21	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000724663	SCV003822290	uncertain significance	not provided	2019-06-21	criteria provided, single submitter	clinical testing