Submissions for variant NM_001384140.1(PCDH15):c.4214G>A (p.Arg1405His)

gnomAD frequency: 0.00008  dbSNP: rs143538460

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000664819	SCV000788836	uncertain significance	Usher syndrome type 1F	2017-01-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001241412	SCV001414426	uncertain significance	not provided	2024-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1405 of the PCDH15 protein (p.Arg1405His). This variant is present in population databases (rs143538460, gnomAD 0.008%). This missense change has been observed in individual(s) with non-syndromic deafness (PMID: 26969326). This variant is also known as NM_001142763:c.4229G>A (p.Arg1410His). ClinVar contains an entry for this variant (Variation ID: 550153). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000664819	SCV003761038	uncertain significance	Usher syndrome type 1F	2023-01-24	criteria provided, single submitter	curation	The p.Arg1405His variant in PCDH15 has been reported in 1 individual, in the compound heterozygous state, with Usher syndrome type 1F (PMID: 26969326) and has been identified in 0.008% (2/24962) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs143538460). This variant has also been reported in ClinVar (Variation ID#: 550153) and has been interpreted as a variant of uncertain significance by Counsyl, Invitae, and Natera, Inc.. 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. 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.Arg1405His variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting (Richards 2015).
GeneDx	RCV001241412	SCV003803381	uncertain significance	not provided	2023-04-25	criteria provided, single submitter	clinical testing	Observed with the PCDH15 N221S variant in a patient with hearing loss in published literature; it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Sloan-Heggen et al., 2016; described as R1410H using alternate nomenclature); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26969326)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004525998	SCV005040067	uncertain significance	not specified	2024-03-07	criteria provided, single submitter	clinical testing	Variant summary: PCDH15 c.4214G>A (p.Arg1405His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 249056 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4214G>A has been reported in the literature as NM_001142763.2:c.4229G>A (p.Arg1410His), in a non-informative genotype in at-least one individual with a clinical diagnosis of autosomal recessive non-syndromic hearing loss (second allele classification and/or phase not clearly specified) (example, Sloan-Heggen_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome Type 1F. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26969326). ClinVar contains an entry for this variant (Variation ID: 550153). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000664819	SCV002092344	uncertain significance	Usher syndrome type 1F	2020-02-14	no assertion criteria provided	clinical testing