Submissions for variant NM_001267550.2(TTN):c.70250T>C (p.Ile23417Thr)

gnomAD frequency: 0.00086  dbSNP: rs201836227

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154922	SCV000204604	benign	not specified	2017-10-23	criteria provided, single submitter	clinical testing	p.Ile20849Thr in exon 275 of TTN: This variant is not expected to have clinical significance because it has been identified in 0.3% (82/23988) of African chromo somes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.o rg; dbSNP rs201836227). ACMG/AMP Criteria applied: BA1 (Richards 2015).
GeneDx	RCV001704125	SCV000237481	likely benign	not provided	2020-06-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30924900)
Eurofins Ntd Llc (ga)	RCV000154922	SCV000337673	likely benign	not specified	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000468387	SCV000555264	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000622225	SCV000737177	likely benign	Cardiovascular phenotype	2018-12-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Athena Diagnostics	RCV000154922	SCV001476367	benign	not specified	2019-10-28	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840140	SCV002100301	benign	Autosomal recessive limb-girdle muscular dystrophy type 2J	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840141	SCV002100303	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840142	SCV002100304	benign	Early-onset myopathy with fatal cardiomyopathy	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840139	SCV002100305	benign	Tibial muscular dystrophy	2021-09-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154922	SCV002500187	benign	not specified	2022-03-07	criteria provided, single submitter	clinical testing	Variant summary: TTN c.62546T>C (p.Ile20849Thr) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 248832 control chromosomes (gnomAD), predominantly at a frequency of 0.0032 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.62546T>C in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Seven ClinVar submitters have assessed the variant since 2014: four have classified the variant as likely benign and three as benign. Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV004544422	SCV004767267	likely benign	TTN-related disorder	2022-03-28	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Clinical Genetics, Academic Medical Center	RCV000154922	SCV001923298	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001704125	SCV001968094	likely benign	not provided		no assertion criteria provided	clinical testing