Submissions for variant NM_001267550.2(TTN):c.105514_105516del (p.Ser35172del)

dbSNP: rs573843615

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000226470	SCV000286409	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-12-27	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000727747	SCV000605505	uncertain significance	not provided	2017-05-31	criteria provided, single submitter	clinical testing	The p.Ser32604del variant (rs573843615) has not been reported in the medical literature nor has it been previously identified in our laboratory; however, it is listed in the ClinVar database as a variant of uncertain significance (Variation ID: 180582). It is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in non-Finnish Europeans of 0.056% (identified in 71 out of 126,608 chromosomes). This variant is an in-frame deletion of a single amino acid in a non-repeat region of TTN protein, and the consequences on protein structure/function are not predictable. Thus, based on the available information, the clinical significance of the p.Ser32604del variant cannot be determined with certainty.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000584782	SCV000692513	likely benign	Hypertrophic cardiomyopathy 1	2017-03-15	criteria provided, single submitter	research	The TTN Ser35172del is an in-frame deletion. This variant is located in the M-band where truncating variants have been associated with DCM. TTN Ser35172del has been observed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at a frequency of 0.0003. We have identified this variant in an HCM case. An additional variant (MYH7 Arg652Gly) was also identified in this individual which is sufficient to explain disease. Given the limited understanding of TTN in-frame deletions particularly in HCM cases, the higher than expected frequency in ExAC, and that another possibly disease-causing variant has been identified in our case, we have classified this as a likely benign variant.
Eurofins Ntd Llc (ga)	RCV000727747	SCV000855124	uncertain significance	not provided	2017-08-31	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198087	SCV001368872	uncertain significance	See cases	2019-02-16	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM4.
Baylor Genetics	RCV001333492	SCV001526084	uncertain significance	Myopathy, myofibrillar, 9, with early respiratory failure	2018-04-05	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV000727747	SCV001812172	likely benign	not provided	2021-06-09	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32880476)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798528	SCV002042340	uncertain significance	Cardiomyopathy	2019-07-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408710	SCV002669262	uncertain significance	Cardiovascular phenotype	2022-03-10	criteria provided, single submitter	clinical testing	The c.78319_78321delTCT variant (also known as p.S26107del) is located in coding exon 185 of the TTN gene. This variant results from an in-frame TCT deletion at nucleotide positions 78319 to 78321. This results in the in-frame deletion of a serine at codon 26107. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort who also had variants in other cardiac-related genes (Verdonschot JAJ et al. Circ Genom Precis Med, 2020 10;13:476-487). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469030	SCV002766514	likely benign	not specified	2022-11-21	criteria provided, single submitter	clinical testing	Variant summary: TTN c.97810_97812delTCT (p.Ser32604del) results in an in-frame deletion that is predicted to remove one amino acids from the encoded protein. The variant allele was found at a frequency of 0.00031 in 249180 control chromosomes, predominantly at a frequency of 0.00052 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.33 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.97810_97812delTCT has been reported in the literature in a DCM cohort listed as a VUS (Verdonschot_2020). This report does 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. 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: six submitters classified the variant as VUS while 2 classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Revvity Omics, Revvity	RCV000727747	SCV003824275	uncertain significance	not provided	2021-09-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000727747	SCV004150172	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing	TTN: PM4:Supporting
Mayo Clinic Laboratories, Mayo Clinic	RCV000727747	SCV004225014	uncertain significance	not provided	2023-02-24	criteria provided, single submitter	clinical testing	BS1
Blueprint Genetics	RCV000157578	SCV000207324	uncertain significance	Left ventricular noncompaction cardiomyopathy	2014-08-28	no assertion criteria provided	clinical testing