Submissions for variant NM_198253.3(TERT):c.2833G>A (p.Asp945Asn)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002636518	SCV003507327	uncertain significance	Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis	2021-08-12	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with asparagine at codon 945 of the TERT protein (p.Asp945Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV004818235	SCV005438902	uncertain significance	Dyskeratosis congenita, autosomal dominant 2	2023-07-22	criteria provided, single submitter	clinical testing	The observed missense variant c.2833G>Ap.Asp945Asn in TERT gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Asp945Asn variant is reported with 0.0004% allele frequency in gnomAD Exomes. It has been submitted to ClinVar as Uncertain Significance. The amino acid Asp at position 945 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance.
Ambry Genetics	RCV004823114	SCV005512381	uncertain significance	Dyskeratosis congenita	2024-10-11	criteria provided, single submitter	clinical testing	The p.D945N variant (also known as c.2833G>A), located in coding exon 11 of the TERT gene, results from a G to A substitution at nucleotide position 2833. The aspartic acid at codon 945 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.