Submissions for variant NM_001384140.1(PCDH15):c.594G>A (p.Pro198=)

gnomAD frequency: 0.00006  dbSNP: rs368308772

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000372702	SCV000363236	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001367556	SCV001563910	uncertain significance	not provided	2022-07-05	criteria provided, single submitter	clinical testing	This sequence change affects codon 198 of the PCDH15 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PCDH15 protein. This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. This variant is present in population databases (rs368308772, gnomAD 0.004%). 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: 300202). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Fulgent Genetics, Fulgent Genetics	RCV002502193	SCV002814977	uncertain significance	Autosomal recessive nonsyndromic hearing loss 23; Usher syndrome type 1D; Usher syndrome type 1F	2021-08-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509358	SCV002819881	uncertain significance	not specified	2022-12-28	criteria provided, single submitter	clinical testing	Variant summary: PCDH15 c.594G>A (p.Pro198Pro) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.4e-05 in 251048 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.594G>A has been reported in the literature in a heterozygous individual affected with Retinitis Pigmentosa (Jespergaard_2019). This report does 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified it as VUS (n=3) and Likely Pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787858	SCV000926873	likely pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Natera, Inc.	RCV001828299	SCV002094328	uncertain significance	Usher syndrome type 1F	2019-11-11	no assertion criteria provided	clinical testing