Submissions for variant NM_001384140.1(PCDH15):c.1339G>A (p.Asp447Asn)

gnomAD frequency: 0.00036  dbSNP: rs150509146

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039700	SCV000063389	uncertain significance	not specified	2014-09-11	criteria provided, single submitter	clinical testing	The Asp447Asn variant in PCDH15 has been previously reported by our laboratory i n 1 individual with hearing loss and delayed walking, but a variant affecting th e remaining copy of PCDH15 was not identified. This variant has been identified in 0.06% (5/8600) of European American chromosomes by the NHLBI Exome Sequencin g Project and in 0.7% (1/1324) chromosomes by the ClinSeq project (http://evs.gs .washington.edu/EVS/; dbSNP rs150509146). Computational prediction tools do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Asp447Asn variant is uncertain.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755595	SCV000604612	uncertain significance	not provided	2017-06-01	criteria provided, single submitter	clinical testing	The p.Asp447Asn variant (rs150509146) has not been reported in the medical literature, nor has it been previously identified in our laboratory; however, it is listed in the ClinVar database as a variant of uncertain significance (Variation ID: 46441). It is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in non-Finnish Europeans of 0.044% (identified in 56 out of 126,490 chromosomes). The aspartic acid at codon 447 is weakly conserved considering 12 species (Alamut software v2.9), and several species of fish have an asparagine at this position suggesting this change is evolutionary tolerated. Likewise, computational analyses suggest this variant does not have a significant effect on PCDH15 protein structure/function (SIFT: tolerated, PolyPhen2: benign). However, based on the available information, the clinical significance of the p.Asp447Asn variant cannot be determined with certainty.
Illumina Laboratory Services, Illumina	RCV001108337	SCV001265563	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000755595	SCV001419184	uncertain significance	not provided	2022-08-16	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 447 of the PCDH15 protein (p.Asp447Asn). This variant is present in population databases (rs150509146, gnomAD 0.04%). 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: 46441). 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.
GeneDx	RCV000755595	SCV002575598	uncertain significance	not provided	2022-09-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15537665)
Fulgent Genetics, Fulgent Genetics	RCV002496639	SCV002807006	uncertain significance	Autosomal recessive nonsyndromic hearing loss 23; Usher syndrome type 1D; Usher syndrome type 1F	2022-02-11	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000755595	SCV004225242	uncertain significance	not provided	2022-08-30	criteria provided, single submitter	clinical testing	BP4, PM2_supporting
CeGaT Center for Human Genetics Tuebingen	RCV000755595	SCV004701829	uncertain significance	not provided	2024-01-01	criteria provided, single submitter	clinical testing	PCDH15: PM2
Natera, Inc.	RCV001275402	SCV001460552	uncertain significance	Usher syndrome type 1F	2020-01-17	no assertion criteria provided	clinical testing