Submissions for variant NM_198253.3(TERT):c.1663G>A (p.Glu555Lys)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002927510	SCV003259862	uncertain significance	Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis	2022-06-27	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 555 of the TERT protein (p.Glu555Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TERT-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TERT protein function. 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	RCV004559986	SCV003911318	uncertain significance	Dyskeratosis congenita	2022-11-30	criteria provided, single submitter	clinical testing	The p.E555K variant (also known as c.1663G>A), located in coding exon 3 of the TERT gene, results from a G to A substitution at nucleotide position 1663. The glutamic acid at codon 555 is replaced by lysine, an amino acid with similar properties. This amino acid position is conserved. 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.
PreventionGenetics, part of Exact Sciences	RCV004545430	SCV004771104	uncertain significance	TERT-related disorder	2024-03-04	no assertion criteria provided	clinical testing	The TERT c.1663G>A variant is predicted to result in the amino acid substitution p.Glu555Lys. To our knowledge, this variant has not been reported in the literature or in gnomAD, indicating this variant is rare. In ClinVar, this variant has been reported as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/2051772/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.