Submissions for variant NM_001267550.2(TTN):c.107593G>A (p.Glu35865Lys)

gnomAD frequency: 0.00001  dbSNP: rs372841288

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000727477	SCV000708900	uncertain significance	not provided	2017-05-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000727477	SCV000718237	uncertain significance	not provided	2023-01-16	criteria provided, single submitter	clinical testing	Reported as c.99889G>A in alternate transcript in patient with unspecified cardiomyopathy in published literature (van Lint et al., 2019); however, no further clinical information was provided; Located in the M-line region of TTN in which the majority of loss of function variants have been associated with autosomal recessive titinopathies (Carmignac et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); Missense variant in a gene in which most reported pathogenic variants are truncating/loss of function; This variant is associated with the following publications: (PMID: 30847666)
Invitae	RCV001349766	SCV001544126	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2022-09-29	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 35865 of the TTN protein (p.Glu35865Lys). This variant is present in population databases (rs372841288, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 502239). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant is located in the M band of TTN (PMID: 25589632). Variants in this region may be relevant for neuromuscular disorders, but have not been definitively shown to cause cardiomyopathy (PMID: 23975875). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002420581	SCV002681164	uncertain significance	Cardiovascular phenotype	2019-07-15	criteria provided, single submitter	clinical testing	The p.E26800K variant (also known as c.80398G>A), located in coding exon 189 of the TTN gene, results from a G to A substitution at nucleotide position 80398. The glutamic acid at codon 26800 is replaced by lysine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000727477	SCV003818483	uncertain significance	not provided	2022-03-25	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000727477	SCV001743109	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000727477	SCV001922635	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000727477	SCV001973037	uncertain significance	not provided		no assertion criteria provided	clinical testing