Submissions for variant NM_001267550.2(TTN):c.53055G>A (p.Met17685Ile)

gnomAD frequency: 0.00074  dbSNP: rs200387466

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152325	SCV000201214	uncertain significance	not specified	2014-07-16	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Met15117Ile var iant in TTN has been identified by our laboratory in 1 African American adult wi th LVH and a family history of cardiomyopathy and one Hispanic child with DCM wh o also carried a likely pathogenic variant in another gene. This variant has be en identified in 0.2% (8/3720) of African American chromosomes by the NHLBI Exom e Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP 200387466). Methi onine (Met) at position 15117 is not conserved in evolution, supporting that a c hange at this position may be tolerated. In summary, while the clinical signific ance of the Met15117Ile variant is uncertain, its frequency and lack of conserva tion suggests that it is more likely to be benign.
GeneDx	RCV000727183	SCV000237286	likely benign	not provided	2020-10-26	criteria provided, single submitter	clinical testing
Invitae	RCV001087840	SCV000555467	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-30	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000727183	SCV000706454	uncertain significance	not provided	2017-10-04	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170609	SCV001333198	benign	Cardiomyopathy	2018-05-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000152325	SCV001519478	likely benign	not specified	2021-03-15	criteria provided, single submitter	clinical testing	Variant summary: TTN c.45351G>A (p.Met15117Ile) results in a conservative amino acid change located in the A-band of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 278948 control chromosomes, predominantly at a frequency of 0.0023 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 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.45351G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as likely benign/benign (n=3) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002453499	SCV002739177	likely benign	Cardiovascular phenotype	2019-01-26	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.
Revvity Omics, Revvity	RCV000727183	SCV003825551	uncertain significance	not provided	2021-06-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004544372	SCV004795956	likely benign	TTN-related disorder	2023-03-27	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).