Submissions for variant NM_015450.3(POT1):c.1442A>G (p.Glu481Gly)

gnomAD frequency: 0.00004  dbSNP: rs548024862

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000696190	SCV000824741	uncertain significance	Tumor predisposition syndrome 3	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 481 of the POT1 protein (p.Glu481Gly). This variant is present in population databases (rs548024862, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with POT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 574289). 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 POT1 protein function with a negative predictive value of 80%. 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	RCV001011602	SCV001171942	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-12	criteria provided, single submitter	clinical testing	The p.E481G variant (also known as c.1442A>G), located in coding exon 11 of the POT1 gene, results from an A to G substitution at nucleotide position 1442. The glutamic acid at codon 481 is replaced by glycine, an amino acid with similar properties. This alteration was identified in 0 of 2928 melanoma cases and 1 of 3298 controls (Simonin-Wilmer I et al. J Med Genet, 2023 Jul;60:692-696). Functional studies suggest this alteration does not impact telomere binding; however, additional evidence is needed to confirm this finding (Simonin-Wilmer I et al. J Med Genet, 2023 Jul;60:692-696). This amino acid position is 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.
GeneDx	RCV001568200	SCV001792027	uncertain significance	not provided	2023-09-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in a control individual and not in any melanoma cases (Simonin-Wilmer et al., 2022); This variant is associated with the following publications: (PMID: 28393830, 36539277)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001568200	SCV004219092	uncertain significance	not provided	2022-05-19	criteria provided, single submitter	clinical testing	To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.00014 (5/35440 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Genetic Services Laboratory, University of Chicago	RCV003151137	SCV003839914	uncertain significance	not specified	2022-07-18	no assertion criteria provided	clinical testing	DNA sequence analysis of the POT1 gene demonstrated a sequence change, c.1442A>G, in exon 15 that results in an amino acid change, p.Glu481Gly. This sequence change does not appear to have been previously described in individuals with POT1-related disorders and has been described in the gnomAD database with a frequency of 0.0039%in the overall population (dbSNP rs548024862). The p.Glu481Gly change affects a moderately conserved amino acid residue located in a domain of the POT1 protein that is not known to be functional. The p.Glu481Gly substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Glu481Gly change remains unknown at this time.