ClinVar Miner

Submissions for variant NM_001384140.1(PCDH15):c.1606G>C (p.Ala536Pro)

gnomAD frequency: 0.00019  dbSNP: rs140516168
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000222497 SCV000272296 uncertain significance not specified 2015-03-06 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Ala536Pro var iant in PCDH15 has not been previously reported in individuals with hearing loss , but has been identified in 0.1% (11/10404) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs140516168 ). The alanine (Ala) at position 536 is not conserved through species, with 2 ma mmals (dolphin and killer whale) having a proline (Pro) at this position, sugges ting that changes at this position may be tolerated. Additional computational pr ediction tools do not provide strong support for or against an impact to the pro tein. In summary, while the clinical significance of the p.Ala536Pro variant is uncertain, the conservation data suggest that it is more likely to be benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756463 SCV000884287 uncertain significance not provided 2017-11-17 criteria provided, single submitter clinical testing The p.Ala536Pro variant (rs140516168) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.05 percent in the African population (identified on 13 out of 24,018 chromosomes) and has been reported to the ClinVar database as a variant of unknown significance (Variation ID: 229135). The alanine at position 536 is moderately conserved considering 12 species (Alamut v2.10) and computational analyses of the effects of the p.Ala536Pro variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Ala536Pro variant with certainty.
Labcorp Genetics (formerly Invitae), Labcorp RCV000756463 SCV001234692 uncertain significance not provided 2022-09-07 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 536 of the PCDH15 protein (p.Ala536Pro). This variant is present in population databases (rs140516168, gnomAD 0.05%). 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: 229135). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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 RCV000756463 SCV001794735 uncertain significance not provided 2023-05-10 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 RCV003165545 SCV003871675 uncertain significance Inborn genetic diseases 2023-03-02 criteria provided, single submitter clinical testing The c.1606G>C (p.A536P) alteration is located in exon 14 (coding exon 13) of the PCDH15 gene. This alteration results from a G to C substitution at nucleotide position 1606, causing the alanine (A) at amino acid position 536 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc. RCV001833213 SCV002088678 uncertain significance Usher syndrome type 1F 2020-02-21 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.