ClinVar Miner

Submissions for variant NM_015450.3(POT1):c.1213G>A (p.Ala405Thr)

gnomAD frequency: 0.00001  dbSNP: rs753851042
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000556726 SCV000655130 uncertain significance Tumor predisposition syndrome 3 2024-01-16 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 405 of the POT1 protein (p.Ala405Thr). This variant is present in population databases (rs753851042, gnomAD 0.006%). 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: 475030). 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 RCV002358603 SCV002660044 uncertain significance Hereditary cancer-predisposing syndrome 2022-09-12 criteria provided, single submitter clinical testing The p.A405T variant (also known as c.1213G>A), located in coding exon 10 of the POT1 gene, results from a G to A substitution at nucleotide position 1213. The alanine at codon 405 is replaced by threonine, an amino acid with similar properties. This amino acid position is not 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.
PreventionGenetics, part of Exact Sciences RCV003403334 SCV004104661 uncertain significance POT1-related condition 2022-08-26 criteria provided, single submitter clinical testing The POT1 c.1213G>A variant is predicted to result in the amino acid substitution p.Ala405Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-124481183-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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