rs137853001

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_033056.4(PCDH15):c.7C>T(p.Arg3Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000994 in 1,610,356 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

PCDH15
NM_033056.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 6.43

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 241 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-54664256-G-A is Pathogenic according to our data. Variant chr10-54664256-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54664256-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_033056.4 linkuse as main transcript	c.7C>T	p.Arg3Ter	stop_gained	2/33	ENST00000320301.11
PCDH15	NM_001384140.1 linkuse as main transcript	c.7C>T	p.Arg3Ter	stop_gained	2/38	ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11 linkuse as main transcript	c.7C>T	p.Arg3Ter	stop_gained	2/33	1	NM_033056.4		Q96QU1-1
PCDH15	ENST00000644397.2 linkuse as main transcript	c.7C>T	p.Arg3Ter	stop_gained	2/38		NM_001384140.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151878

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000201

AC:

AN:

248430

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134318

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000661

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1458478

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

725554

show subpopulations

Gnomad4 AFR exome

AF:

0.0000900

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000581

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000541

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151878

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74178

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00000982

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Usher syndrome type 1F

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Dec 15, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 15, 2017	Variant summary: The PCDH15 c.7C>T (p.Arg3X) variant results in a premature termination codon, predicted to cause a truncated or absent PCDH15 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One truncation downstream of this position have been classified as pathogenic by our laboratory (e.g. c.733C>T, p.Arg245X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/108974 control chromosomes at a frequency of 0.0000092, which does not exceed the estimated maximal expected allele frequency of a pathogenic PCDH15 variant (0.0031623). This variant has been reported in multiple studies in patients with USH syndrome, in both homozygotes and heterozygotes (Ahmed_AJHG_2001, Jaijo_BMB_2010, Roux_Invest Ophthalmol Vis Sci_2011), with the UMD-PCDH15 database reporting this variant in 14 patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 21, 2020	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 24, 2023	The p.Arg3Ter variant in PCDH15 has been reported in 4 individuals with Usher syndrome type 1F (PMID: 11487575, 18719945, 27460420, 31541171), segregated with disease in 5 affected relatives from 2 families (PMID: 18719945, 11487575), and has been identified in 0.007% (2/30248) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs137853001). 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. This variant has also been reported in ClinVar (Variation ID#: 4931) and has been interpreted as pathogenic or likely pathogenic by multiple laboratories. Of the 4 affected individuals, 3 of those were homozygotes, which increases the likelihood that the p.Arg3Ter variant is pathogenic (PMID: 11487575, 18719945, 27460420). This nonsense variant leads to a premature termination codon at position 3, which is predicted to lead to a truncated or absent protein. Loss of function of the PCDH15 gene is an established disease mechanism in autosomal recessive Usher syndrome type 1F. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome type 1F. ACMG/AMP Criteria applied: PVS1, PM3, PM2_supporting, PP1_strong (Richards 2015). -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 23, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 4931). This premature translational stop signal has been observed in individuals with Usher syndrome (PMID: 11487575, 25404053, 27440999, 27460420). This variant is present in population databases (rs137853001, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Arg3*) in the PCDH15 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCDH15 are known to be pathogenic (PMID: 11398101, 11487575, 14570705). -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2016	- -

Autosomal recessive nonsyndromic hearing loss 23

Pathogenic:2

Pathogenic, no assertion criteria provided	case-control	Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	Feb 26, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 12, 2023	- -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 07, 2017

The p.Arg3X variant in PCDH15 has been reported in 10 individuals with Usher syn drome (including 7 homozygous and 1 compound heterozygous) and segregated with d isease in 10 affected relatives from 2 families (Alagramam 2001, Roux 2011, Ahme d 2008, Ahmed 2001, Aparisi 2014, Bonnet 2016, Jaijo 2009, Perreault-Micale 2014 ). This variant has been identified in (1/14512) of Asian chromosomes by the Exo me Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs1378530 01); however, this low frequency in the general population is consistent with th e carrier frequency for recessive hearing loss. This nonsense variant leads to a premature termination codon at position 3, which is predicted to lead to a trun cated or absent protein. Loss of PCDH15 function is an established disease mecha nism for Usher syndrome. In summary, this variant meets criteria to be classifie d as pathogenic for autosomal recessive Usher syndrome based on its presence in the homozygous or compound heterozygous state in multiple affected individuals, segregation with disease in multiple affected relatives, extremely low frequency in the general population, and its predicted impact on the protein. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.63

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.79

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.95

MutationTaster

Benign

1.0

A;A;A;A;A;A;A;A;A;A;A;A;A;A;A;A

Vest4

0.73

GERP RS

5.8

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over