Submissions for variant NM_001267550.2(TTN):c.75527G>A (p.Arg25176His)

gnomAD frequency: 0.00013  dbSNP: rs375693396

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000294438	SCV000337103	uncertain significance	not provided	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000459157	SCV000542560	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-07-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618051	SCV000736542	likely benign	Cardiovascular phenotype	2020-08-25	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.
Fulgent Genetics, Fulgent Genetics	RCV000764316	SCV000895335	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000294438	SCV001248648	uncertain significance	not provided	2019-12-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000294438	SCV001715758	uncertain significance	not provided	2021-02-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000294438	SCV001815432	likely benign	not provided	2020-10-12	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31983221)
Revvity Omics, Revvity	RCV000294438	SCV003819795	uncertain significance	not provided	2022-11-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235176	SCV003934124	uncertain significance	not specified	2023-05-15	criteria provided, single submitter	clinical testing	Variant summary: TTN c.67823G>A (p.Arg22608His) results in a non-conservative amino acid change located in the A-band of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 248354 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00011 vs 0.00039), allowing no conclusion about variant significance. c.67823G>A has been reported in the literature in an individual affected with Dilated Cardiomyopathy (Mazzarotto_2020). 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: 31983221). Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=6) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000294438	SCV004564933	uncertain significance	not provided	2023-10-11	criteria provided, single submitter	clinical testing	The TTN c.75527G>A; p.Arg25176His variant (rs375693396; ClinVar Variation ID: 284466) is rare in the general population (<1% 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.Arg25176His 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). Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. Linke and Hamdani. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068.