Submissions for variant NM_001267550.2(TTN):c.96989T>C (p.Ile32330Thr)

gnomAD frequency: 0.00009  dbSNP: rs201023432

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000154036	SCV000203672	uncertain significance	not provided	2016-04-11	criteria provided, single submitter	clinical testing
Invitae	RCV000233400	SCV000286941	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-02-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362807	SCV002664003	likely benign	Cardiovascular phenotype	2020-02-21	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	RCV002483330	SCV002789727	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	2021-10-08	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000154036	SCV003818506	uncertain significance	not provided	2022-04-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000154036	SCV004150210	uncertain significance	not provided	2022-06-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000154036	SCV004225782	uncertain significance	not provided	2022-05-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488402	SCV004241308	uncertain significance	not specified	2023-12-18	criteria provided, single submitter	clinical testing	Variant summary: TTN c.89285T>C (p.Ile29762Thr) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.1e-05 in 247660 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (6.1e-05 vs 0.00039), allowing no conclusion about variant significance. c.89285T>C has been reported in the literature in individuals affected with Dilated Cardiomyopathy and hypertrophic Cardiomyopathy without strong evidence for causality (examples, Lopes_2013, Mazzarotto_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23396983, 31983221). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=6; Likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.