ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.53055G>A (p.Met17685Ile) (rs200387466)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare 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 (; 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 RCV000152325 SCV000237286 likely benign not specified 2018-02-05 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.
Invitae RCV001087840 SCV000555467 likely benign Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2020-12-02 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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.

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