Submissions for variant NM_001267550.2(TTN):c.64811G>A (p.Arg21604Gln)

gnomAD frequency: 0.00024  dbSNP: rs188996850

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155827	SCV000205538	likely benign	not specified	2013-06-14	criteria provided, single submitter	clinical testing	Arg19036Gln in exon 259 of TTN: This variant is not expected to have clinical si gnificance because it has been identified in 2.7% (3/110) of Puerto Rican chromo somes by the 1000 Genomes Project (dbSNP rs188996850). In addition, several othe r species (guinea pig, tetradon, fugu, and medaka) carry a glutamine (Gln) at th is position. Arg19036Gln in exon 259 of TTN (rs188996850; allele frequency = 2. 7%, 3/110)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000476685	SCV000542319	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2018-01-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000733639	SCV000725412	likely benign	not provided	2020-12-03	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000733639	SCV000861729	uncertain significance	not provided	2018-06-12	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769975	SCV000901401	uncertain significance	Cardiomyopathy	2016-09-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002345509	SCV002622328	likely benign	Cardiovascular phenotype	2020-03-05	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000155827	SCV002766511	uncertain significance	not specified	2022-11-15	criteria provided, single submitter	clinical testing	Variant summary: TTN c.57107G>A (p.Arg19036Gln) results in a conservative amino acid change located in the A-band region of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 248302 control chromosomes (gnomAD). To our knowledge, no occurrence of c.57107G>A in individuals affected with Limb-Girdle Muscular Dystrophy, Type 2J and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV000733639	SCV003825880	likely benign	not provided	2023-02-24	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000733639	SCV005876878	uncertain significance	not provided	2024-06-27	criteria provided, single submitter	clinical testing	The TTN c.64811G>A; p.Arg21604Gln variant (rs188996850; ClinVar Variation ID: 179043) is rare in the general population (<0.2% allele frequency in the Genome Aggregation Database) and has not been reported in the medical literature in association with dilated cardiomyopathy (DCM) or other TTN-related disease. The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Thus, the clinical significance of the p.Arg21604Gln variant cannot be determined with certainty. References: Begay RL et al. Role of Titin Missense Variants in Dilated Cardiomyopathy. J Am Heart Assoc. 2015 Nov 13;4(11). PMID: 26567375. Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. PMID: 22335739. Linke WA and Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068. PMID: 24625729.