Submissions for variant NM_001267550.2(TTN):c.15860C>T (p.Thr5287Met)

gnomAD frequency: 0.00076  dbSNP: rs148551876

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000222088	SCV000270975	likely benign	not specified	2015-06-04	criteria provided, single submitter	clinical testing	p.Thr4043Met in exon 51 of TTN: This variant is not expected to have clinical si gnificance because it has been identified in 0.3% (33/9780) of African chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs148551876).
Invitae	RCV000560779	SCV000642714	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-25	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000222088	SCV000701150	likely benign	not specified	2016-11-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000222088	SCV000730337	likely benign	not specified	2017-12-05	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000222088	SCV001426793	benign	not specified	2020-07-13	criteria provided, single submitter	clinical testing	Variant summary: TTN c.12128C>T (p.Thr4043Met) results in a non-conservative amino acid change located in the I-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 0.00028 in 248540 control chromosomes, predominantly at a frequency of 0.0036 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 6-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. c.12128C>T has been reported in the literature in a pediatric patient affected with Dilated Cardiomyopathy who also carried a PKP2 pathogenic variant (c.663C>A, p.Y221X; Headrick_2019). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. An additional co-occurrence with a pathogenic variant has been reported via internal testing (TTR c.424G>A, p.Val142Ile). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Genome-Nilou Lab	RCV001840333	SCV002100055	benign	Autosomal recessive limb-girdle muscular dystrophy type 2J	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840334	SCV002100057	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840335	SCV002100058	benign	Early-onset myopathy with fatal cardiomyopathy	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840332	SCV002100059	benign	Tibial muscular dystrophy	2021-09-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003937844	SCV004755379	likely benign	TTN-related condition	2020-03-09	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).