Submissions for variant NM_001384140.1(PCDH15):c.2102C>T (p.Ala701Val)

gnomAD frequency: 0.00013  dbSNP: rs199537178

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151632	SCV000199859	uncertain significance	not specified	2015-08-07	criteria provided, single submitter	clinical testing	The p.Ala701Val variant in PCDH15 has been previously reported by our laboratory in one individual with mild to moderate sensorineural hearing loss; however, a second variant affecting the remaining copy of PCDH15 was not identified in that individual (LMM unpublished data). This variant has been identified in 13/6654 8 European chromosomes by the Exome Aggregation consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs199537178). Computational prediction tools and conserv ation analysis do not provide strong support for or against an impact to the pro tein. In summary, the clinical significance of the p.Ala701Val variant is uncert ain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001245383	SCV001418667	uncertain significance	not provided	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 701 of the PCDH15 protein (p.Ala701Val). This variant is present in population databases (rs199537178, gnomAD 0.03%). 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: 164921). 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 not expected to disrupt PCDH15 protein function. 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	RCV001245383	SCV002601179	uncertain significance	not provided	2024-07-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported without a second PCDH15 variant in a proband with bilateral sensorineural hearing loss who also had multiple variants in other hearing loss-associated genes (PMID: 29907799); This variant is associated with the following publications: (PMID: 15537665, 29907799)
Fulgent Genetics, Fulgent Genetics	RCV000477800	SCV002814541	uncertain significance	Autosomal recessive nonsyndromic hearing loss 23; Usher syndrome type 1D; Usher syndrome type 1F	2021-08-27	criteria provided, single submitter	clinical testing
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477800	SCV000536860	uncertain significance	Autosomal recessive nonsyndromic hearing loss 23; Usher syndrome type 1D; Usher syndrome type 1F	2015-04-07	no assertion criteria provided	research
Natera, Inc.	RCV001273399	SCV001456433	uncertain significance	Usher syndrome type 1F	2020-01-24	no assertion criteria provided	clinical testing