Submissions for variant NM_001267550.2(TTN):c.98098+3G>A

gnomAD frequency: 0.00003  dbSNP: rs556524594

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725064	SCV000333697	uncertain significance	not provided	2015-09-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000357207	SCV000525202	likely benign	not specified	2016-03-12	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000468276	SCV000542773	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2016-05-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002365300	SCV002663889	likely benign	Cardiovascular phenotype	2019-07-24	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.
Revvity Omics, Revvity	RCV000725064	SCV003821681	uncertain significance	not provided	2019-02-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000725064	SCV004150204	likely benign	not provided	2022-09-01	criteria provided, single submitter	clinical testing	TTN: BP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000357207	SCV005039422	benign	not specified	2024-03-12	criteria provided, single submitter	clinical testing	Variant summary: TTN c.90394+3G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00012 in 237840 control chromosomes, predominantly at a frequency of 0.0016 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.90394+3G>A has been reported in the literature in individuals affected with HCM as well as in the controls in a case-control study (Zhang_2017). These report(s) do 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 have been ascertained in the context of this evaluation (PMID: 28822653). ClinVar contains an entry for this variant (Variation ID: 282305). Based on the evidence outlined above, the variant was classified as benign.