Submissions for variant NM_001267550.2(TTN):c.40973A>G (p.Lys13658Arg)

gnomAD frequency: 0.00012  dbSNP: rs184713215

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154955	SCV000204637	uncertain significance	not specified	2013-07-17	criteria provided, single submitter	clinical testing	The Lys11090Arg variant in TTN has not been reported in individuals with cardiom yopathy, but has been identified in 2/8212 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs18471 321). Computational analyses (biochemical amino acid properties, conservation, A lignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an i mpact to the protein. Additional information is needed to fully assess the clini cal significance of this variant.
Ambry Genetics	RCV000252544	SCV000318390	uncertain significance	Cardiovascular phenotype	2013-03-18	criteria provided, single submitter	clinical testing	There is insufficient or conflicting evidence for classification of this alteration.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000467649	SCV000542275	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-12-21	criteria provided, single submitter	clinical testing
GeneDx	RCV001697149	SCV000718515	likely benign	not provided	2020-02-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23396983)
Illumina Laboratory Services, Illumina	RCV001134532	SCV001294279	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-04-27	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	RCV001135955	SCV001295767	uncertain significance	Dilated cardiomyopathy 1G	2017-04-27	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	RCV001135956	SCV001295768	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2017-04-27	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	RCV001135957	SCV001295769	benign	Tibial muscular dystrophy	2017-04-27	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	RCV001135958	SCV001295770	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2017-04-27	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154955	SCV001821501	likely benign	not specified	2024-07-30	criteria provided, single submitter	clinical testing	Variant summary: TTN c.33269A>G (p.Lys11090Arg) results in a conservative amino acid change located in the I-band region of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 1602136 control chromosomes in the gnomAD database (v4.1 dataset). In addition, within the South Asian subpopulation (allele frequency: 0.00037) the variant was fond in 1 homozygote. Furthermore, in certain ethnicities, e.g. in the Middle Eastern, the variant was reported with an even higher frequency (i.e. 0.0025), and which is about 6-times higher than the estimated maximum expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00039), suggesting that the variant might be benign. The variant, c.33269A>G, has been reported in the literature in one individual affected with hypertrophic cardiomyopathy (Lopes_2013). These report(s) 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 publication have been ascertained in the context of this evaluation (PMID: 23396983). ClinVar contains an entry for this variant (Variation ID: 178220). Based on the evidence outlined above, the variant was classified as likely benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798508	SCV002042466	uncertain significance	Cardiomyopathy	2019-07-08	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001697149	SCV003823590	uncertain significance	not provided	2023-12-16	criteria provided, single submitter	clinical testing