rs565693539

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_033056.4(PCDH15):c.679C>T(p.Arg227Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000256 in 1,601,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R227L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

PCDH15
NM_033056.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 5.25

Publications

1 publications found

Variant links:

Genes affected

PCDH15 (HGNC:14674): (protocadherin related 15) This gene is a member of the cadherin superfamily. Family members encode integral membrane proteins that mediate calcium-dependent cell-cell adhesion. It plays an essential role in maintenance of normal retinal and cochlear function. Mutations in this gene result in hearing loss and Usher Syndrome Type IF (USH1F). Extensive alternative splicing resulting in multiple isoforms has been observed in the mouse ortholog. Similar alternatively spliced transcripts are inferred to occur in human, and additional variants are likely to occur. [provided by RefSeq, Dec 2008]

PCDH15 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 23
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
Usher syndrome type 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 1F
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
nonsyndromic genetic hearing loss
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

PCDH15 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.751

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4 link	c.679C>T	p.Arg227Cys	missense_variant	Exon 7 of 33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1 link	c.679C>T	p.Arg227Cys	missense_variant	Exon 7 of 38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11 link	c.679C>T	p.Arg227Cys	missense_variant	Exon 7 of 33	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2 link	c.679C>T	p.Arg227Cys	missense_variant	Exon 7 of 38		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151796

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000679

AC:

AN:

250380

AF XY:

0.0000443

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000377

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000234

AC:

AN:

1449988

Hom.:

Cov.:

AF XY:

0.0000180

AC XY:

AN XY:

722084

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33156

American (AMR)

AF:

0.000470

AC:

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26012

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39550

South Asian (SAS)

AF:

0.00

AC:

AN:

86002

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53322

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00000726

AC:

AN:

1101570

Other (OTH)

AF:

0.0000500

AC:

AN:

59978

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000461

AC:

AN:

151914

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41532

American (AMR)

AF:

0.000197

AC:

AN:

15210

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000442

AC:

AN:

67798

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000247

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Jun 11, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 227 of the PCDH15 protein (p.Arg227Cys). This variant is present in population databases (rs565693539, gnomAD 0.04%). 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: 179459). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

May 02, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method: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 -

not specified

Uncertain:1

Oct 09, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg227Cys variant in PCDH15 has been identified in the heterozygous state in two individuals with hearing loss, one of whom had clinical features of Usher syndrome but was found to have an alternate genetic etiology (LMM data). This v ariant has also been identified in 0.04% (14/34350) of Latino chromosomes by gno mAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variati on ID 179459). Computational prediction tools and conservation analysis do not p rovide strong support for or against an impact to the protein. In summary, the c linical significance of the p.Arg227Cys variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting. -

Usher syndrome type 1F

Uncertain:1

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Mar 26, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.679C>T (p.R227C) alteration is located in exon 7 (coding exon 6) of the PCDH15 gene. This alteration results from a C to T substitution at nucleotide position 679, causing the arginine (R) at amino acid position 227 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;.;.;.;.;T;.;.;T;.;T;.;.;T;T;.;.;.;.;.;.;D;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.97

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.75

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.31

MutationAssessor

Pathogenic

3.0

.;.;.;.;M;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;M;M

PhyloP100

5.2

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-5.8

D;.;.;.;.;.;D;D;.;D;.;D;D;.;.;.;D;D;D;.;D;D;D

REVEL

Uncertain

0.42

Sift

Pathogenic

0.0

D;.;.;.;.;.;D;D;.;D;.;D;D;.;.;.;D;D;D;.;D;D;D

Sift4G

Pathogenic

0.0010

D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0, 1.0, 1.0

.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;D;D;D;.;D;D;D

Vest4

0.69

MutPred

0.63

Loss of MoRF binding (P = 0.0662);Loss of MoRF binding (P = 0.0662);.;Loss of MoRF binding (P = 0.0662);Loss of MoRF binding (P = 0.0662);.;Loss of MoRF binding (P = 0.0662);Loss of MoRF binding (P = 0.0662);Loss of MoRF binding (P = 0.0662);Loss of MoRF binding (P = 0.0662);.;Loss of MoRF binding (P = 0.0662);Loss of MoRF binding (P = 0.0662);.;.;Loss of MoRF binding (P = 0.0662);Loss of MoRF binding (P = 0.0662);Loss of MoRF binding (P = 0.0662);.;.;Loss of MoRF binding (P = 0.0662);Loss of MoRF binding (P = 0.0662);Loss of MoRF binding (P = 0.0662);

MVP

0.79

MPC

0.24

ClinPred

0.88

GERP RS

4.5

Varity_R

0.24

gMVP

0.66

Mutation Taster

=46/54

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over