Submissions for variant NM_001267550.2(TTN):c.4645+8G>T

gnomAD frequency: 0.00029  dbSNP: rs144456585

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000176695	SCV000228392	likely benign	not specified	2015-02-06	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000176695	SCV000271037	likely benign	not specified	2015-07-09	criteria provided, single submitter	clinical testing	c.4645+8G>T in Intron 26 of TTN: This variant is not expected to have clinical s ignificance because it is not located within the splice consensus sequence. It h as been identified in 0.15% (14/9232) of African chromosomes by the Exome Aggreg ation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs144456585).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000550606	SCV000643218	benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000176695	SCV000722246	likely benign	not specified	2018-02-20	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.
Genome-Nilou Lab	RCV001840251	SCV002101496	benign	Autosomal recessive limb-girdle muscular dystrophy type 2J	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840252	SCV002101497	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840253	SCV002101498	benign	Early-onset myopathy with fatal cardiomyopathy	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840250	SCV002101499	benign	Tibial muscular dystrophy	2021-09-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000176695	SCV004020346	benign	not specified	2023-06-12	criteria provided, single submitter	clinical testing	Variant summary: TTN c.4645+8G>T 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 9.3e-05 in 247318 control chromosomes, predominantly at a frequency of 0.0013 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3 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.4645+8G>T in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Clinical Genetics, Academic Medical Center	RCV000176695	SCV001920869	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001726021	SCV001964724	likely benign	not provided		no assertion criteria provided	clinical testing