Submissions for variant NM_015450.3(POT1):c.64A>G (p.Ile22Val)

gnomAD frequency: 0.00019  dbSNP: rs375440229

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000504020	SCV000596553	uncertain significance	not specified	2016-08-19	criteria provided, single submitter	clinical testing
Invitae	RCV000541787	SCV000655197	uncertain significance	Tumor predisposition syndrome 3	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 22 of the POT1 protein (p.Ile22Val). This variant is present in population databases (rs375440229, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with aplastic anemia (PMID: 30523342). ClinVar contains an entry for this variant (Variation ID: 436392). 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	RCV000573872	SCV000674396	likely benign	Hereditary cancer-predisposing syndrome	2018-09-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
GeneDx	RCV001548286	SCV001768168	uncertain significance	not provided	2023-07-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with aplastic anemia who had telomere length within normal limits (Gutierrez-Rodrigues et al., 2019); This variant is associated with the following publications: (PMID: 30523342, 28393830)
Sema4, Sema4	RCV000573872	SCV002527170	likely benign	Hereditary cancer-predisposing syndrome	2020-11-10	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000504020	SCV002550287	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001548286	SCV001926565	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001548286	SCV001972213	likely benign	not provided		no assertion criteria provided	clinical testing