Submissions for variant NM_033056.4(PCDH15):c.4812G>T (p.Arg1604Ser)

gnomAD frequency: 0.00066  dbSNP: rs148718874

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000215424	SCV000269625	benign	not specified	2015-10-20	criteria provided, single submitter	clinical testing	p.Arg1604Ser in exon 33 of PCDH15: This variant is not expected to have clinical significance because it has been identified in 2.75% (238/8654) of East Asian c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; rs148718874).
Illumina Laboratory Services, Illumina	RCV000287812	SCV000363137	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx	RCV000839178	SCV000981062	benign	not provided	2019-05-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26166082, 29625443, 31180159, 33090715)
Invitae	RCV000839178	SCV001055465	benign	not provided	2024-01-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002500691	SCV002810226	likely benign	Autosomal recessive nonsyndromic hearing loss 23; Usher syndrome type 1D; Usher syndrome type 1F	2022-04-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000215424	SCV004021255	likely benign	not specified	2023-06-28	criteria provided, single submitter	clinical testing	Variant summary: PCDH15 c.4812G>T (p.Arg1604Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 251356 control chromosomes, predominantly at a frequency of 0.028 within the East Asian subpopulation in the gnomAD database, including 12 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCDH15 causing Usher Syndrome Type 1F phenotype (0.0032), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.4812G>T has been reported in the literature in individuals affected with poor cochlear implants outcome and vestibular dysfunction (examples: Wu_2015 and Guan_2021) and one of these reports classified the variant as VUS (Guan_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome Type 1F. The following publications have been ascertained in the context of this evaluation (PMID: 26166082, 34416374). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and benign/ likely benign (n=6). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000839178	SCV004125391	benign	not provided	2022-12-01	criteria provided, single submitter	clinical testing	PCDH15: BP4, BS1, BS2
Natera, Inc.	RCV001272402	SCV001454387	benign	Usher syndrome type 1F	2020-01-06	no assertion criteria provided	clinical testing
WangQJ Lab, Chinese People's Liberation Army General Hospital	RCV001822855	SCV001762502	uncertain significance	Autosomal recessive nonsyndromic hearing loss 23	2021-07-01	no assertion criteria provided	clinical testing