Submissions for variant NM_002700.3(POU4F3):c.490C>T (p.Pro164Ser)

gnomAD frequency: 0.00014  dbSNP: rs372436251

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155274	SCV000204960	uncertain significance	not specified	2013-05-31	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Pro164Ser varia nt in POU4F3 has not been reported in individuals with hearing loss, but has bee n identified in 0.02% (2/8598) of European American chromosomes by the NHLBI Exo me Sequencing Project (http://evs.gs.washington.edu/EVS/). Although this varian t has been seen in the general population, its frequency is not high enough to r ule out a pathogenic role. Computational analyses (biochemical amino acid proper ties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Pro164Ser v ariant may not impact the protein, though this information is not predictive eno ugh to rule out pathogenicity. In summary, the clinical significance of this var iant cannot be determined with certainty; however, based upon the computational data, we lean towards a more likely benign role.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850126	SCV002213477	uncertain significance	not provided	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 164 of the POU4F3 protein (p.Pro164Ser). This variant is present in population databases (rs372436251, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with POU4F3-related conditions. ClinVar contains an entry for this variant (Variation ID: 178526). 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 POU4F3 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	RCV003338431	SCV004059424	uncertain significance	Inborn genetic diseases	2023-08-04	criteria provided, single submitter	clinical testing	The c.490C>T (p.P164S) alteration is located in exon 2 (coding exon 2) of the POU4F3 gene. This alteration results from a C to T substitution at nucleotide position 490, causing the proline (P) at amino acid position 164 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004754319	SCV005349207	likely benign	POU4F3-related disorder	2024-08-24	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).