Submissions for variant NM_001267550.2(TTN):c.39296-13C>T

gnomAD frequency: 0.00099  dbSNP: rs372380420

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154958	SCV000204640	benign	not specified	2015-07-29	criteria provided, single submitter	clinical testing	c.31994-13C>T in intron 158 of TTN: This variant is not expected to have clinica l significance because a C>T change at this position does not diverge from the s plice consensus sequence and is therefore unlikely to impact splicing. It has be en identified in 0.3% (26/8354) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org/; dbSNP rs372380420).
GeneDx	RCV000154958	SCV000515125	benign	not specified	2015-09-10	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154958	SCV001431963	benign	not specified	2020-08-24	criteria provided, single submitter	clinical testing	Variant summary: TTN c.31994-13C>T alters a non-conserved 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 0.00024 in 241980 control chromosomes, predominantly at a frequency of 0.0036 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 9-fold 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.31994-13C>T in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Genome-Nilou Lab	RCV001840152	SCV002101227	benign	Autosomal recessive limb-girdle muscular dystrophy type 2J	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840153	SCV002101228	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840154	SCV002101229	benign	Early-onset myopathy with fatal cardiomyopathy	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840151	SCV002101230	benign	Tibial muscular dystrophy	2021-09-10	criteria provided, single submitter	clinical testing
Invitae	RCV002056067	SCV002368598	benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-02-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001726010	SCV003800030	likely benign	not provided	2022-03-08	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000154958	SCV001921889	benign	not specified		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001726010	SCV001963508	likely benign	not provided		no assertion criteria provided	clinical testing