Submissions for variant NM_001384140.1(PCDH15):c.2138A>G (p.Asn713Ser)

gnomAD frequency: 0.00001  dbSNP: rs190878515

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000267122	SCV000340490	uncertain significance	not provided	2016-03-16	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000294986	SCV000363197	uncertain significance	Usher syndrome type 1	2018-01-12	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	RCV000267122	SCV003472901	uncertain significance	not provided	2022-07-11	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 713 of the PCDH15 protein (p.Asn713Ser). This variant is present in population databases (rs190878515, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of PCDH15-related conditions (PMID: 31054281). This variant is also known as c.2153A>G (p.Asn718Ser). ClinVar contains an entry for this variant (Variation ID: 286893). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002519268	SCV003761104	uncertain significance	Usher syndrome type 1F	2023-01-24	criteria provided, single submitter	curation	The p.Asn713Ser variant in PCDH15 has not been previously reported in the literature in individuals with Usher syndrome type 1F but has been identified in 0.005% (1/18380) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs190878515). 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#: 286893) and has been interpreted as a variant of uncertain significance by Eurofins NTD LLC (GA) and Illumina Laboratory Services (Illumina). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Asn713Ser variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting (Richards 2015).