Submissions for variant NM_001267550.2(TTN):c.9707C>T (p.Pro3236Leu)

gnomAD frequency: 0.00014  dbSNP: rs146199720

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172453	SCV000051335	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000412686	SCV000238065	uncertain significance	not specified	2015-12-01	criteria provided, single submitter	clinical testing	Missense variants in the TTN gene are considered 'unclassified' if they are not previously reported in the literature and do not have >1% frequency in the population to be considered a polymorphism. Research indicates that truncating mutations in the TTN gene are expected to account for approximately 25% of familial and 18% of sporadic idiopathic DCM; however, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles. There has been little investigation into non-truncating variants. (Herman D et al. Truncations of titin causing dilated cardiomyopathy. N Eng J Med 366:619-628, 2012) The variant is found in DCM panel(s).
Invitae	RCV000526576	SCV000643969	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-11-30	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000172453	SCV000706275	uncertain significance	not provided	2017-02-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000412686	SCV001554603	uncertain significance	not specified	2023-05-08	criteria provided, single submitter	clinical testing	Variant summary: TTN c.9707C>T (p.Pro3236Leu) results in a non-conservative amino acid change located in the I-band region (cardiodb.org) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 249166 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00014 vs 0.00039), allowing no conclusion about variant significance. To our knowledge, there are no reports of c.9707C>T in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating an impact on protein function published in the literature. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000172453	SCV002544182	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002381564	SCV002694642	likely benign	Cardiovascular phenotype	2020-06-15	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Fulgent Genetics, Fulgent Genetics	RCV002485115	SCV002783201	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9	2021-08-27	criteria provided, single submitter	clinical testing