Submissions for variant NM_001384140.1(PCDH15):c.1169A>G (p.Asn390Ser)

gnomAD frequency: 0.00002  dbSNP: rs397517450

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039696	SCV000063385	uncertain significance	not specified	2010-10-07	criteria provided, single submitter	clinical testing	The Asn390Ser variant in PCDH15 has not been reported in the literature nor prev iously identified by our laboratory. This residue is conserved across species an d computational analyses (homology, PolyPhen, SIFT, AlignGVGD) suggest that the Asn390Ser variant may impact the protein. However, this information is not predi ctive enough to assume pathogenicity. It should be noted that this lab has only sequenced the PCDH15 in 170 patients and limited controls such that the full spe ctrum of benign variation has not yet been defined for this gene, increasing the possibility that this may be a benign variant. In summary, the clinical signifi cance of this variant cannot be determined with certainty at this time.
Illumina Laboratory Services, Illumina	RCV001103159	SCV001259880	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	RCV001340857	SCV001534690	uncertain significance	not provided	2022-07-19	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 390 of the PCDH15 protein (p.Asn390Ser). This variant is present in population databases (rs397517450, gnomAD 0.009%), including at least one homozygous and/or hemizygous individual. 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: 46437). 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: "Probably Damaging"; 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.
Genome-Nilou Lab	RCV001578651	SCV001805913	uncertain significance	Autosomal recessive nonsyndromic hearing loss 23	2021-07-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001578652	SCV001805914	uncertain significance	Usher syndrome type 1F	2021-07-14	criteria provided, single submitter	clinical testing
GeneDx	RCV001340857	SCV002601156	uncertain significance	not provided	2022-11-08	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
Ambry Genetics	RCV003298077	SCV004002259	uncertain significance	Inborn genetic diseases	2023-06-06	criteria provided, single submitter	clinical testing	The c.1169A>G (p.N390S) alteration is located in exon 11 (coding exon 10) of the PCDH15 gene. This alteration results from a A to G substitution at nucleotide position 1169, causing the asparagine (N) at amino acid position 390 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV001578652	SCV002091814	uncertain significance	Usher syndrome type 1F	2019-11-11	no assertion criteria provided	clinical testing