Submissions for variant NM_001267550.2(TTN):c.76987G>A (p.Asp25663Asn)

gnomAD frequency: 0.00037  dbSNP: rs143186270

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172635	SCV000054934	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000260684	SCV000237564	likely benign	not specified	2017-12-08	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.
Ambry Genetics	RCV000249719	SCV000319131	likely benign	Cardiovascular phenotype	2020-06-10	criteria provided, single submitter	clinical testing	In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Eurofins Ntd Llc (ga)	RCV000172635	SCV000332115	uncertain significance	not provided	2015-06-11	criteria provided, single submitter	clinical testing
Invitae	RCV001080773	SCV000765380	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-31	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000172635	SCV001146489	likely benign	not provided	2018-10-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000260684	SCV002572023	likely benign	not specified	2023-11-20	criteria provided, single submitter	clinical testing	Variant summary: TTN c.69283G>A (p.Asp23095Asn) 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 0.0001 in 248306 control chromosomes, predominantly at a frequency of 0.00084 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 2-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 African or African-American origin. To our knowledge, no occurrence of c.69283G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (likely benign, n = 4; uncertain significance, n = 2). Based on the evidence outlined above, the variant was classified as likely benign.
Revvity Omics, Revvity	RCV000172635	SCV003818496	uncertain significance	not provided	2022-01-25	criteria provided, single submitter	clinical testing