Submissions for variant NM_001267550.2(TTN):c.84461C>T (p.Pro28154Leu)

gnomAD frequency: 0.00238  dbSNP: rs200350579

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040706	SCV000064397	likely benign	not specified	2015-06-25	criteria provided, single submitter	clinical testing	p.Pro25586Leu in exon 275 of TTN: This variant is not expected to have clinical significance because it has been identified in 0.85% (83/9754) of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org) .
Eurofins Ntd Llc (ga)	RCV000040706	SCV000114461	benign	not specified	2013-05-29	criteria provided, single submitter	clinical testing
GeneDx	RCV001703909	SCV000237653	likely benign	not provided	2021-03-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226402	SCV000286873	benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-29	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000040706	SCV000616157	benign	not specified	2017-01-24	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769918	SCV000901344	benign	Cardiomyopathy	2023-01-09	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852802	SCV000995529	likely benign	Heart failure	2018-07-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040706	SCV001370715	likely benign	not specified	2024-02-20	criteria provided, single submitter	clinical testing	Variant summary: TTN c.76757C>T (p.Pro25586Leu) 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 0.00053 in 243108 control chromosomes, predominantly at a frequency of 0.0083 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 13-fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), 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.76757C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. The following publication have been ascertained in the context of this evaluation (PMID: 27843123). ClinVar contains an entry for this variant (Variation ID: 47437). Based on the evidence outlined above, the variant was classified as likely benign.
Genome-Nilou Lab	RCV001839709	SCV002102316	benign	Autosomal recessive limb-girdle muscular dystrophy type 2J	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001839710	SCV002102318	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001839711	SCV002102319	benign	Early-onset myopathy with fatal cardiomyopathy	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001839708	SCV002102320	benign	Tibial muscular dystrophy	2021-09-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002345325	SCV002649650	benign	Cardiovascular phenotype	2018-10-30	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
CeGaT Center for Human Genetics Tuebingen	RCV001703909	SCV004699646	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	TTN: BS1
Clinical Genetics, Academic Medical Center	RCV000040706	SCV001918431	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000040706	SCV001966698	benign	not specified		no assertion criteria provided	clinical testing