Submissions for variant NM_001267550.2(TTN):c.89018G>A (p.Arg29673Gln)

gnomAD frequency: 0.00010  dbSNP: rs200639218

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172210	SCV000051277	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152193	SCV000200939	uncertain significance	not specified	2014-12-04	criteria provided, single submitter	clinical testing	The p.Arg27105Gln variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 3/8262 European American chromo somes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs200639218). Computational prediction tools and conservation analysis sug gest that this variant may impact the protein, though this information is not pr edictive enough to determine pathogenicity. In summary, the clinical significanc e of the p.Arg27105Gln variant is uncertain.
Invitae	RCV000532604	SCV000643858	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-07-25	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000172210	SCV000855249	uncertain significance	not provided	2018-02-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765549	SCV000896864	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	RCV000172210	SCV001780053	likely benign	not provided	2019-06-24	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000172210	SCV003826720	uncertain significance	not provided	2023-12-07	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149922	SCV003837961	benign	Cardiomyopathy	2022-02-16	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000172210	SCV001550582	uncertain significance	not provided		no assertion criteria provided	clinical testing	The TTN p.Arg27105Gln variant was not identified in the literature but was identified in dbSNP (ID: rs200639218) and ClinVar (classified as uncertain signifcance by Invitae, Laboratory for Molecular Medicine, Fulgent Genetics, EGL Genetics and Biesecker Lab/Clinical Genomics Section, National Institutes of Health). The variant was identified in control databases in 60 of 279880 chromosomes at a frequency of 0.0002144 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 29 of 35362 chromosomes (freq: 0.00082), Other in 2 of 7114 chromosomes (freq: 0.000281), South Asian in 8 of 30600 chromosomes (freq: 0.000261), European (non-Finnish) in 19 of 127734 chromosomes (freq: 0.000149), Ashkenazi Jewish in 1 of 10334 chromosomes (freq: 0.000097) and East Asian in 1 of 19526 chromosomes (freq: 0.000051), but was not observed in the African or European (Finnish) populations. The p.Arg27105 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000172210	SCV001799187	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000172210	SCV001923788	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172210	SCV001972516	uncertain significance	not provided		no assertion criteria provided	clinical testing