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

gnomAD frequency: 0.00059  dbSNP: rs200317412

Total submissions: 11

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082619	SCV000555026	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2025-01-01	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: 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.
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	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	2025-03-18	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). c.64883G>A has been reported in the literature in an individual affected with Hypertrophic Cardiomyopathy, without strong 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). ClinVar contains an entry for this variant (Variation ID: 178191). Based on the evidence outlined above, the variant was classified as likely benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000154921	SCV006068446	benign	not specified	2025-04-09	criteria provided, single submitter	clinical testing	BS1;BP1
PreventionGenetics, part of Exact Sciences	RCV004534972	SCV004744201	likely benign	TTN-related disorder	2022-02-24	no assertion criteria provided	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).