Submissions for variant NM_001267550.2(TTN):c.64903C>T (p.Arg21635Cys)

gnomAD frequency: 0.00005  dbSNP: rs201614524

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040485	SCV000064176	uncertain significance	not specified	2012-10-08	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Arg19067Cys var iant in TTN has been identified in 2/8240 European American chromosomes from a b road population by the NHLBI Exome Sequencing Project (http://evs.gs.washington. edu/EVS/). This variant was also identified in one individual with DCM who had t wo other variants, including a TTN variant inherited in cis with this variant. F amily studies suggest that the TTN variants may be less likely disease causing b ut computational analyses (biochemical amino acid properties, conservation, Alig nGVGD, PolyPhen2, and SIFT) suggest that the Arg19067Cys variant may impact the protein (please note: the accuracy of these tools is unknown and this informatio n is not predictive enough to determine pathogenicity). Additional information i s needed to fully assess the clinical significance of the Arg19067Cys variant.
GeneDx	RCV001356315	SCV000725317	likely benign	not provided	2019-04-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24503780)
Baylor Genetics	RCV001336915	SCV001530436	uncertain significance	Myopathy, myofibrillar, 9, with early respiratory failure	2018-01-24	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity	RCV001356315	SCV003824941	uncertain significance	not provided	2019-11-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040485	SCV004020354	uncertain significance	not specified	2023-06-13	criteria provided, single submitter	clinical testing	Variant summary: TTN c.57199C>T (p.Arg19067Cys) results in a non-conservative amino acid change located in the A-band of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 248496 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (6e-05 vs 0.00039), allowing no conclusion about variant significance. c.57199C>T has been reported in the literature in an individual affected with Dilated Cardiomyopathy (Pugh_2014) without strong evidence for causality. 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: 24503780). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=2) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356315	SCV001551449	uncertain significance	not provided		no assertion criteria provided	clinical testing	The TTN p.Arg19994Cys variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs201614524) and ClinVar (classified as likely benign by GeneDx and uncertain significance by Laboratory for Molecular Medicine). The variant was identified in control databases in 17 of 279872 chromosomes (1 homozygous) at a frequency of 0.00006074 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: East Asian in 5 of 19474 chromosomes (freq: 0.000257), European (non-Finnish) in 10 of 127774 chromosomes (freq: 0.000078), African in 1 of 24194 chromosomes (freq: 0.000041) and Latino in 1 of 35352 chromosomes (freq: 0.000028), but was not observed in the Ashkenazi Jewish, European (Finnish), Other, or South Asian populations. The p.Arg19994 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.