ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.72587G>A (p.Arg24196His)

gnomAD frequency: 0.00063  dbSNP: rs200317412
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000154921 SCV000204603 likely benign not specified 2013-09-12 criteria provided, single submitter clinical testing Arg21628His in exon 275 of TTN: This variant is not expected to have clinical si gnificance because it has been identified in 0.3% (12/3854) of African American chromosomes from by the NHLBI Exome Sequencing Project (http://evs.gs.washington .edu/EVS/; dbSNP rs200317412). Arg21628His in exon 275 of TTN (rs200317412); al lele frequency = 0.3% 12/3854) **
GeneDx RCV000727739 SCV000237514 likely benign not provided 2020-10-02 criteria provided, single submitter clinical testing
Invitae RCV001082619 SCV000555026 likely benign Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2024-01-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000621332 SCV000737211 likely benign Cardiovascular phenotype 2019-12-04 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: 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.
Eurofins Ntd Llc (ga) RCV000727739 SCV000855113 uncertain significance not provided 2018-05-23 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000769954 SCV000901380 benign Cardiomyopathy 2017-10-30 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000154921 SCV001476372 benign not specified 2020-02-19 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000727739 SCV002049584 likely benign not provided 2020-10-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000154921 SCV002571017 likely benign not specified 2022-07-05 criteria provided, single submitter clinical testing Variant summary: TTN c.64883G>A (p.Arg21628His) results in a non-conservative amino acid change located in the A-band of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 166950 control chromosomes, predominantly at a frequency of 0.0028 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 7 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. c.64883G>A has been reported in the literature in individuals affected with HCM. This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign n=2, likely benign n=4, VUS n=1). Based on the evidence outlined above, the variant was classified as likely benign.

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