Submissions for variant NM_198253.3(TERT):c.1409G>A (p.Arg470His)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV004559479	SCV002699225	likely benign	Dyskeratosis congenita	2022-04-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003108072	SCV003780519	uncertain significance	Dyskeratosis congenita, autosomal dominant 2; Idiopathic Pulmonary Fibrosis	2023-07-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 470 of the TERT protein (p.Arg470His). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with TERT-related conditions. ClinVar contains an entry for this variant (Variation ID: 1771970). 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 not 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.
PreventionGenetics, part of Exact Sciences	RCV004534080	SCV004120874	uncertain significance	TERT-related disorder	2022-08-28	criteria provided, single submitter	clinical testing	The TERT c.1409G>A variant is predicted to result in the amino acid substitution p.Arg470His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0031% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-1293592-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.