Submissions for variant NM_001384140.1(PCDH15):c.944C>T (p.Pro315Leu)

gnomAD frequency: 0.00004  dbSNP: rs138299477

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001045508	SCV001209364	uncertain significance	not provided	2022-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 315 of the PCDH15 protein (p.Pro315Leu). This variant is present in population databases (rs138299477, gnomAD 0.02%). This missense change has been observed in individual(s) with hearing loss (PMID: 23967202). ClinVar contains an entry for this variant (Variation ID: 842988). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Illumina Laboratory Services, Illumina	RCV001105073	SCV001261991	uncertain significance	Usher syndrome type 1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553688	SCV001774646	uncertain significance	not specified	2021-07-20	criteria provided, single submitter	clinical testing	Variant summary: PCDH15 c.944C>T (p.Pro315Leu) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251392 control chromosomes, predominantly at a frequency of 0.00022 within the East Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.944C>T has been reported in the literature as a non-informative genotype in at-least one Japanese individual affected with Deafness (example, Miyagawa_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome Type 1F. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001045508	SCV001986026	uncertain significance	not provided	2024-09-10	criteria provided, single submitter	clinical testing	Observed in one patient with early onset hearing loss in published literature, however, additional information was not available (PMID: 23967202); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30245029, 23967202)
Natera, Inc.	RCV001276786	SCV001463334	uncertain significance	Usher syndrome type 1F	2020-09-16	no assertion criteria provided	clinical testing