ClinVar Miner

Submissions for variant NM_033056.4(PCDH15):c.4846A>G (p.Thr1616Ala)

gnomAD frequency: 0.00001  dbSNP: rs751863041
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000825425 SCV000966723 uncertain significance not specified 2018-02-26 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Thr1616Ala va riant in PCDH15 has not been previously reported in individuals with hearing los s, but has been identified in 1/33576 Latino chromosomes by the Genome Aggregati on Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs751863041). Altho ugh this variant has been seen in the general population, its frequency is not h igh enough to rule out a pathogenic role. Threonine at position 1616 is not cons erved in mammals or evolutionarily distant species, raising the possibility that a change at this position may be tolerated. Additional computational prediction tools suggest that the p.Thr1616Ala variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Thr1616Ala variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: PM 2; BP4.
Labcorp Genetics (formerly Invitae), Labcorp RCV001347012 SCV001541252 uncertain significance not provided 2021-09-01 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 1616 of the PCDH15 protein (p.Thr1616Ala). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs751863041, ExAC 0.02%). This variant has not been reported in the literature in individuals affected with PCDH15-related conditions. ClinVar contains an entry for this variant (Variation ID: 666902). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Natera, Inc. RCV001830837 SCV002089182 uncertain significance Usher syndrome type 1F 2021-05-28 no assertion criteria provided clinical testing

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