Submissions for variant NM_001267550.2(TTN):c.59474G>C (p.Arg19825Thr)

gnomAD frequency: 0.00006  dbSNP: rs376465623

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000528644	SCV000643448	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-12-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174706	SCV001337969	uncertain significance	not specified	2020-01-20	criteria provided, single submitter	clinical testing	Variant summary: TTN c.51770G>C (p.Arg17257Thr) results in a non-conservative amino acid change located in the A-band domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 248454 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Cardiomyopathy (6.4e-05 vs 0.00063), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.51770G>C in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002448714	SCV002611375	likely benign	Cardiovascular phenotype	2019-06-17	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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	RCV002506347	SCV002814164	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	2021-09-27	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537986	SCV004715262	uncertain significance	TTN-related disorder	2024-01-12	criteria provided, single submitter	clinical testing	The TTN c.59474G>C variant is predicted to result in the amino acid substitution p.Arg19825Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001703197	SCV001929345	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001703197	SCV001955789	likely benign	not provided		no assertion criteria provided	clinical testing