Submissions for variant NM_198253.3(TERT):c.2072G>A (p.Arg691His)

dbSNP: rs202123213

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479321	SCV000573963	uncertain significance	not provided	2017-03-07	criteria provided, single submitter	clinical testing	The R691H variant in the TERT gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R691H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R691H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R691H as a variant of uncertain significance.
Invitae	RCV002526972	SCV000650727	uncertain significance	Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis	2021-08-30	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 424177). This missense change has been observed in individual(s) with clinical features of TERT-related conditions (Invitae). This variant is present in population databases (rs202123213, ExAC 0.05%). This sequence change replaces arginine with histidine at codon 691 of the TERT protein (p.Arg691His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV003338610	SCV004047619	uncertain significance	Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1		criteria provided, single submitter	clinical testing	The missense variant in c.2072G>A(p.Arg691His) in TERT gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Arg691His variant is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance (VUS). The amino acid Arg at position 691 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS).