Submissions for variant NM_001267550.2(TTN):c.89314G>A (p.Glu29772Lys)

gnomAD frequency: 0.00019  dbSNP: rs200503016

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172209	SCV000054903	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Ambry Genetics	RCV000242895	SCV000319633	likely benign	Cardiovascular phenotype	2022-01-26	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.
Genetic Services Laboratory, University of Chicago	RCV000499612	SCV000597684	uncertain significance	not specified	2016-03-04	criteria provided, single submitter	clinical testing
Invitae	RCV000528669	SCV000643866	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-07-25	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000172209	SCV000844785	uncertain significance	not provided	2017-08-28	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000172209	SCV000855112	uncertain significance	not provided	2018-02-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765548	SCV000896863	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	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000172209	SCV000981676	likely benign	not provided	2019-10-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000172209	SCV001152680	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	TTN: BP4
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798612	SCV002043044	likely benign	Cardiomyopathy	2019-11-21	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000172209	SCV003821806	uncertain significance	not provided	2021-10-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000499612	SCV004020363	uncertain significance	not specified	2023-06-26	criteria provided, single submitter	clinical testing	Variant summary: TTN c.81610G>A (p.Glu27204Lys) results in a conservative amino acid change located in the A-band domain of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-04 in 248480 control chromosomes (gnomAD), predominantly in the non-Finnish European population at a frequency of 3.6e-04 in 112394 chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00025 vs 0.00039), allowing no conclusion about variant significance. c.81610G>A has been reported in the literature in individuals affected with Dilated Cardiomyopathy, Hypertrophic cardiomyopathy, or preeclampsia without evidence for causality (examples: Forleo_2017, Mates_2018, Mademont-Soler_2017, Horvat_2019, Gammill_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. However, co-occurrences with other pathogenic variant(s) have been reported (TTN c.94322delT, p.L31441*) in at least one individual affected with Dilated Cardiomyopathy (example: Forleo_2017), providing supporting evidence for a benign role. 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: 28750076, 30021846, 29892087, 28771489, 29511324). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=6) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
New York Genome Center	RCV003335176	SCV004046640	uncertain significance	Dilated cardiomyopathy 1G; Hypertrophic cardiomyopathy 9	2022-12-20	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000172209	SCV001744839	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000172209	SCV001922385	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000172209	SCV001959755	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172209	SCV001975759	likely benign	not provided		no assertion criteria provided	clinical testing