ClinVar Miner

Submissions for variant NM_015450.3(POT1):c.1186G>A (p.Asp396Asn)

gnomAD frequency: 0.00004  dbSNP: rs148956533
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000563999 SCV000674391 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-30 criteria provided, single submitter clinical testing The p.D396N variant (also known as c.1186G>A), located in coding exon 10 of the POT1 gene, results from a G to A substitution at nucleotide position 1186. The aspartic acid at codon 396 is replaced by asparagine, an amino acid with highly 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.
Invitae RCV000685095 SCV000812567 uncertain significance Tumor predisposition syndrome 3 2024-01-05 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 396 of the POT1 protein (p.Asp396Asn). This variant is present in population databases (rs148956533, 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: 486129). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
GeneDx RCV001551887 SCV001772486 uncertain significance not provided 2023-10-03 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30556179, 28393830, 36539277)

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