Submissions for variant NM_015450.3(POT1):c.916A>G (p.Ile306Val)

gnomAD frequency: 0.00001  dbSNP: rs1415345156

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001212356	SCV001383939	uncertain significance	Tumor predisposition syndrome 3	2023-01-05	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. 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. ClinVar contains an entry for this variant (Variation ID: 942376). This variant has not been reported in the literature in individuals affected with POT1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 306 of the POT1 protein (p.Ile306Val).
Genetic Services Laboratory, University of Chicago	RCV001819900	SCV002066757	uncertain significance	not specified	2021-01-11	criteria provided, single submitter	clinical testing	DNA sequence analysis of the POT1 gene demonstrated a sequence change, c.916A>G, in exon 11 that results in an amino acid change, p.Ile306Val. 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 in two individuals with an overall population frequency of 0.0008% (dbSNP rs1415345156). The p.Ile306Val 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.Ile306Val substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ile306Val change remains unknown at this time.
Ambry Genetics	RCV002375169	SCV002686147	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-02	criteria provided, single submitter	clinical testing	The p.I306V variant (also known as c.916A>G), located in coding exon 7 of the POT1 gene, results from an A to G substitution at nucleotide position 916. The isoleucine at codon 306 is replaced by valine, 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001702887	SCV001931393	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001702887	SCV001976156	likely benign	not provided		no assertion criteria provided	clinical testing