Submissions for variant NM_001384140.1(PCDH15):c.2539G>A (p.Asp847Asn)

gnomAD frequency: 0.00001  dbSNP: rs751941551

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000374290	SCV000363193	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	RCV002520605	SCV003452896	uncertain significance	not provided	2024-02-23	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 847 of the PCDH15 protein (p.Asp847Asn). This variant is present in population databases (rs751941551, gnomAD 0.004%). This missense change has been observed in individual(s) with non-syndromic hearing loss (PMID: 26969326). ClinVar contains an entry for this variant (Variation ID: 300189). 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 expected to disrupt PCDH15 protein function with a positive 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002520604	SCV003761065	uncertain significance	Usher syndrome type 1F	2023-01-24	criteria provided, single submitter	curation	The p.Asp847Asn variant in PCDH15 has been reported in 1 individual, in the compound heterozygous state, with Usher syndrome type 1F (PMID: 26969326) and has been identified in 0.004% (1/24952) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs751941551). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 300189) and has been interpreted as a variant of uncertain significance by Illumina Laboratory Services (Illumina). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Asp847Asn variant is uncertain. ACMG/AMP Criteria applied: PP3, PM2_supporting (Richards 2015).