ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.74549A>G (p.Asp24850Gly)

gnomAD frequency: 0.00002  dbSNP: rs573415766
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Total submissions: 12
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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 RCV000216300 SCV000272755 uncertain significance not specified 2015-04-29 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Asp22282Gly v ariant in TTN has not been previously reported in individuals with cardiomyopath y, but has been identified in 0.25% (41/16430) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs573 415766). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, while the c linical significance of the p.Asp22282Gly variant is uncertain, its frequency su ggests that it is more likely to be benign.
Eurofins Ntd Llc (ga) RCV000725210 SCV000335014 uncertain significance not provided 2015-09-15 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000328950 SCV000421819 uncertain significance Myopathy, myofibrillar, 9, with early respiratory failure 2016-06-14 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000376348 SCV000421820 uncertain significance Hypertrophic cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000284422 SCV000421821 uncertain significance Early-onset myopathy with fatal cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000341722 SCV000421822 uncertain significance Tibial muscular dystrophy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000396489 SCV000421823 uncertain significance Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000278714 SCV000421824 uncertain significance Limb-Girdle Muscular Dystrophy, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV001086254 SCV000555156 likely benign Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2024-01-24 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000725210 SCV001146481 benign not provided 2018-11-01 criteria provided, single submitter clinical testing
GeneDx RCV000725210 SCV001823239 likely benign not provided 2021-02-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000216300 SCV002104060 likely benign not specified 2022-02-14 criteria provided, single submitter clinical testing Variant summary: TTN c.66845A>G (p.Asp22282Gly) 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 0.00032 in 247022 control chromosomes, predominantly at a frequency of 0.0026 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 6.7 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 South Asian origin. To our knowledge, no occurrence of c.66845A>G in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=3; VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign.

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