Submissions for variant NM_001267550.2(TTN):c.39301G>A (p.Glu13101Lys)

gnomAD frequency: 0.00021  dbSNP: rs201035457

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040194	SCV000063885	likely benign	not specified	2021-03-30	criteria provided, single submitter	clinical testing	The p.Glu10667Lys variant in TTN is classified as likely benign because it has been identified in 0.04% (55/124348) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BS1.
GeneDx	RCV000725460	SCV000237130	likely benign	not provided	2021-03-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23396983, 24503780)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228887	SCV000286633	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-12-19	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000725460	SCV000337111	uncertain significance	not provided	2017-09-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000725460	SCV000884802	uncertain significance	not provided	2018-05-14	criteria provided, single submitter	clinical testing	The TTN: c.31999G>A; p.Glu10667Lys variant is rare in the general population (<1% allele frequency in the Genome Aggregation Database) and have 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. While the clinical significance of such variants is considered uncertain, evidence suggests that the vast majority of missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Given the available evidence, the clinical significance of the p.Arg13618Leu and p.Ala7671Gly variants cannot be determined with certainty.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798148	SCV002042461	likely benign	Cardiomyopathy	2023-03-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000725460	SCV003819799	uncertain significance	not provided	2019-05-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040194	SCV003845067	likely benign	not specified	2024-12-09	criteria provided, single submitter	clinical testing	Variant summary: TTN c.31999G>A (p.Glu10667Lys) results in a conservative amino acid change located in the I-band region of the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 241906 control chromosomes, predominantly at a frequency of 0.00045 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039). c.31999G>A has been reported in the literature in individuals affected with Dilated Cardiomyopathy (Pugh_2014) and Hypertrophic Cardiomyopathy (Lopes_2013) . These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. Co-occurrence with another pathogenic variant has been reported (MYH7 c.2722C>G, p.Leu908Val, internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23396983, 24503780). ClinVar contains an entry for this variant (Variation ID: 46924). Based on the evidence outlined above, the variant was classified as likely benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000040194	SCV006065371	likely benign	not specified	2025-04-09	criteria provided, single submitter	clinical testing	BS1;BP1
Clinical Genetics, Academic Medical Center	RCV000725460	SCV001920373	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000725460	SCV001965747	uncertain significance	not provided		no assertion criteria provided	clinical testing