ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.97418G>A (p.Arg32473His)

gnomAD frequency: 0.00001  dbSNP: rs397517770
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Total submissions: 5
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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 RCV000040854 SCV000064545 benign not specified 2019-03-13 criteria provided, single submitter clinical testing The p.Arg29905His variant in TTN is classified as benign because it has been identified in 0.13% (40/30508) of South Asian chromosomes and 3 homozygotes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1.
GeneDx RCV000726674 SCV000237831 likely benign not provided 2020-12-16 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000726674 SCV000702070 uncertain significance not provided 2018-08-14 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001088882 SCV001053375 likely benign Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2024-01-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000040854 SCV003934171 likely benign not specified 2023-05-18 criteria provided, single submitter clinical testing Variant summary: TTN c.89714G>A (p.Arg29905His) results in a non-conservative amino acid change located in the A-band region 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 0.00017 in 247808 control chromosomes (gnomAD), predominantly at a frequency of 0.0013 within the South Asian subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.89714G>A has been reported in the literature in one individual affected with Hypertrophic Cardiomyopathy without evidence for causality (Burstein_2021). 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. The following publication has been ascertained in the context of this evaluation (PMID: 32746448). Four ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, two as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as likely benign.

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