Submissions for variant NM_001267550.2(TTN):c.16055-9A>C

gnomAD frequency: 0.00108  dbSNP: rs368897883

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039881	SCV000063572	likely benign	not specified	2012-01-24	criteria provided, single submitter	clinical testing	c.12323-9A>C in intron 51 of TTN: This variant is not expected to have clinical significance because has been identified in 0.4% (12/3172) of African American c hromosomes by the NHLBI Exome Sequencing Project in a broad population (http://e vs.gs.washington.edu/EVS).
Eurofins Ntd Llc (ga)	RCV000039881	SCV000114330	likely benign	not specified	2015-08-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000039881	SCV000515093	benign	not specified	2015-08-14	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.
Invitae	RCV000468200	SCV000555493	benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-24	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000039881	SCV000616005	benign	not specified	2016-10-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001811283	SCV002049661	likely benign	not provided	2021-07-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001839504	SCV002100047	benign	Autosomal recessive limb-girdle muscular dystrophy type 2J	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001839505	SCV002100048	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001839506	SCV002100049	benign	Early-onset myopathy with fatal cardiomyopathy	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001839503	SCV002100050	benign	Tibial muscular dystrophy	2021-09-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039881	SCV002571880	benign	not specified	2022-08-08	criteria provided, single submitter	clinical testing	Variant summary: TTN c.12323-9A>C alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational 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 0.00036 in 218472 control chromosomes, predominantly at a frequency of 0.0047 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 12 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.12323-9A>C in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as benign (n=4) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign.