Submissions for variant NM_001384140.1(PCDH15):c.2361TGT[2] (p.Val790del)

dbSNP: rs483352837

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000220485	SCV000272298	uncertain significance	not specified	2020-09-10	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Val790del variant in PCDH15 has been previously reported in the homozygous state in one individual with sensorineural hearing loss and segregated in an affected family member. The affected individuals were reported to be age 18 and 28 years, and did not report symptoms of night-blindness. However, electroretinograms were not obtained (Zhan 2015 PMID: 25930172). It has also been identified in one individual with hearing loss by our laboratory who was heterozygous for the variant. This variant has been reported in ClinVar (Variation ID 126521), and it also has been identified in several populations by gnomAD, with the highest frequency of 0.01% (3/19950) of East Asian European chromosomes (http://gnomad.broadinstitute.org). This variant is a deletion of a valine (Val) residue at position 790 and is not predicted to alter the protein reading-frame. It is unclear whether this deletion impacts the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Val790del variant is uncertain. ACMG/AMP criteria applied: PM3_Supporting, PM2_Supporting, PP1, PM4_Supporting.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000114410	SCV000746395	uncertain significance	Autosomal recessive nonsyndromic hearing loss 23	2023-12-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000675146	SCV000800745	uncertain significance	Usher syndrome type 1F	2018-04-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000220485	SCV002511910	uncertain significance	not specified	2022-04-05	criteria provided, single submitter	clinical testing	Variant summary: PCDH15 c.2367_2369delTGT (p.Val790del) results in an in-frame deletion that is predicted to remove one amino acid from Cadherin-like domain (IPR002126, also known as EC7 domain (Zhan_2015)) the encoded protein. The variant allele was found at a frequency of 5.6e-05 in 251246 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PCDH15 causing Usher Syndrome Type 1F (5.6e-05 vs 0.0032), allowing no conclusion about variant significance. c.2367_2369delTGT has been reported in the literature in one heterozygous individual affected with Usher Syndrome and one homozygous individual affected with non-syndromic hearing loss (Zhan_2015, Zheng_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002514567	SCV003266889	uncertain significance	not provided	2022-07-19	criteria provided, single submitter	clinical testing	This variant, c.2367_2369del, results in the deletion of 1 amino acid(s) of the PCDH15 protein (p.Val790del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs483352837, gnomAD 0.02%). This variant has been observed in individual(s) with PCDH15-related conditions (PMID: 25930172, 32835555). ClinVar contains an entry for this variant (Variation ID: 126521). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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	RCV000675146	SCV003761068	uncertain significance	Usher syndrome type 1F	2023-01-24	criteria provided, single submitter	curation	The p.Val790del variant in PCDH15 has been reported in 2 individuals with Usher syndrome type 1F (PMID: 32835555, 25930172) and has been identified in 0.02% (3/19950) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs483352837). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 126521) and has been interpreted as pathogenic by Genomic Research Center (Shahid Beheshti University of Medical Sciences) and Institute of Otorhinolaryngology (Sun Yat-sen University) and as a variant of uncertain significance by Counsyl, Laboratory for Molecular Medicine (Mass General Brigham Personalized Medicine), Natera, Inc, and Women's Health and Genetics/Laboratory Corporation of America. Of the 2 affected individuals, 1 of those was a homozygote, which increases the likelihood that the p.Val790del variant is pathogenic (PMID: 25930172). This variant is a deletion of 1 amino acid at position 790 and is not predicted to alter the protein reading-frame. It is unclear if this deletion will impact the protein. In summary, the clinical significance of the p.Val790del variant is uncertain. ACMG/AMP Criteria applied: PM4_supporting, PM3_supporting (Richards 2015).
GeneDx	RCV002514567	SCV005080996	likely pathogenic	not provided	2023-11-16	criteria provided, single submitter	clinical testing	In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25930172, 32835555)
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796017	SCV005418625	uncertain significance	Autosomal recessive nonsyndromic hearing loss 23; Usher syndrome type 1D; Usher syndrome type 1F		criteria provided, single submitter	clinical testing	PM4+PM3+PM2_Supporting
Institute of Otorhinolaryngology, The First affiliated hospital, Sun Yat-sen University	RCV000114410	SCV000148342	pathogenic	Autosomal recessive nonsyndromic hearing loss 23		flagged submission	not provided	Converted during submission to Pathogenic.
Natera, Inc.	RCV000675146	SCV002088455	uncertain significance	Usher syndrome type 1F	2020-03-10	no assertion criteria provided	clinical testing