Submissions for variant NM_001384140.1(PCDH15):c.575A>G (p.Gln192Arg)

gnomAD frequency: 0.00007  dbSNP: rs201496062

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000284389	SCV000363240	uncertain significance	Usher syndrome type 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000826010	SCV000967498	uncertain significance	not specified	2018-08-21	criteria provided, single submitter	clinical testing	The p.Gln192Arg variant in PCDH15 has not been previously reported in individual s with hearing loss or Usher syndrome but has been identified in 0.01% (4/25744) of Finnish chromosomes and 0.0079% (10/126568) of European chromosomes by the G enome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs20 1496062). This variant has also been reported in ClinVar (Variation ID 300203). Computational prediction tools and conservation analysis suggest that the p.Gln1 92Arg variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Gln192Arg variant is uncertain. ACMG/AMP Criteria applied: PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001038040	SCV001201481	uncertain significance	not provided	2022-08-09	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 192 of the PCDH15 protein (p.Gln192Arg). This variant is present in population databases (rs201496062, gnomAD 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: 300203). 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: "Benign"; 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.
Ambry Genetics	RCV003258747	SCV003949834	uncertain significance	Inborn genetic diseases	2023-06-01	criteria provided, single submitter	clinical testing	The c.575A>G (p.Q192R) alteration is located in exon 6 (coding exon 5) of the PCDH15 gene. This alteration results from a A to G substitution at nucleotide position 575, causing the glutamine (Q) at amino acid position 192 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV001828300	SCV002094339	uncertain significance	Usher syndrome type 1F	2019-11-11	no assertion criteria provided	clinical testing