NM_033056.4:c.733C>T

Variant names:

• chr10-54317414-G-A
• rs111033260
• NM_033056.4:c.733C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_033056.4(PCDH15):​c.733C>T​(p.Arg245*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,613,722 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R245R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: PCDH15 NM_033056.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:23 O:2
• Conservation: PhyloP100: 3.33
• Publications: 48 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 10-54317414-G-A is Pathogenic according to our data. Variant chr10-54317414-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 4933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.733C>T	p.Arg245*	stop_gained	Exon 8 of 33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.733C>T	p.Arg245*	stop_gained	Exon 8 of 38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.733C>T	p.Arg245*	stop_gained	Exon 8 of 33	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.733C>T	p.Arg245*	stop_gained	Exon 8 of 38		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152036 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000223 AC: 56 AN: 251064 AF XY: 0.000184

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000124 AC: 181 AN: 1461686 Hom.: 0 Cov.: 32 AF XY: 0.000110 AC XY: 80 AN XY: 727150

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.000224 AC: 10 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00421 AC: 110 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1111870

Other (OTH) AF: 0.000397 AC: 24 AN: 60384

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152036 Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7 AN XY: 74242

African (AFR) AF: 0.00 AC: 0 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000166 Hom.: 0

Bravo AF: 0.000113

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:23 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

Feb 01, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PCDH15 p.Arg250* variant is known to cause autosomal recessive type 1 Usher syndrome, especially in the Ashkenazi Jewish population (Perreault-Micale_2014_PMID:25307757; Ben-Yosef_2003_PMID:12711741; Brownstein_2004_PMID:15028842). The variant was identified in dbSNP (ID: rs111033260), Cosmic, LOVD 3.0 and in ClinVar (classified as pathogenic by GeneD, Counsyl, Integrated Genetics, Children's Hospital of Philadelphia Division of Human Genetics and Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine for Usher syndrome types 1G, 1, 1D, 1F). The variant was also identified in control databases in 57 of 282438 chromosomes at a frequency of 0.000202 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 45 of 10358 chromosomes (freq: 0.004344), Latino in 8 of 35398 chromosomes (freq: 0.000226), Other in 1 of 7218 chromosomes (freq: 0.000139) and European (non-Finnish) in 3 of 128826 chromosomes (freq: 0.000023); it was not observed in the African, East Asian, European (Finnish) and South Asian populations. The c.748C>T variant leads to a premature stop codon at position 240, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PCDH15 gene are an established mechanism of disease in Usher syndrome and, when found in the homozygous or compound heterozygous state with another pathogenic variant, is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 10, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20301442, 12711741, 15028842, 25525159, 25262649, 27460420, 29490346, 22815625, 30337596, 31456290) -

Jan 13, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg245*) 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). This variant is present in population databases (rs111033260, gnomAD 0.4%). This premature translational stop signal has been observed in individuals with Usher syndrome (PMID: 12711741, 22815625, 27460420). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 12711741, 22815625, 27460420). ClinVar contains an entry for this variant (Variation ID: 4933). For these reasons, this variant has been classified as Pathogenic. -

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PCDH15: PVS1, PM2 -

Usher syndrome type 1F Pathogenic:6

Jun 17, 2015

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Apr 28, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The variant of interest causes a nonsense mutation in exon 8 rresulting in a premature termination codon, a known mechanism for disease, as these types of variants are predicted to cause transcript degradation through nonsense mediated decay or produce a truncated protein. This variant is found in 43/124454 control chromosomes at a frequency of 0.0003455, which does not exceed the maximal expected frequency of a pathogenic allele (0.0031623). The variant of interest has predominantly been observed in Ashkenazi jewish affected individuals via publications. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic. -

Apr 24, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 07, 2018

Laboratory of Prof. Karen Avraham, Tel Aviv University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Recessive, congenital, profound HL; USH1F -

Jan 24, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Arg245Ter variant in PCDH15 has been reported in at least 10 individuals with Usher syndrome type 1F (PMID: 12711741, 29490346, 34416374), segregated with disease in 4 affected relatives from 2 families (PMID: 12711741), and has been identified in 0.4% (45/10358) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs111033260). This variant is a known founder in the Ashkenazi Jewish population, and 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#: 4933) and has been interpreted as pathogenic by multiple submitters. Of the many affected individuals, at least 2 of those were homozygotes, which increases the likelihood that the p.Arg245Ter variant is pathogenic (VariationID: 1185088; PMID: 12711741, 34416374). This nonsense variant leads to a premature termination codon at position 245, 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, PP1_strong (Richards 2015). -

Usher syndrome type 1 Pathogenic:2 Other:1

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Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Usher syndrome type 1D;C1836027:Autosomal recessive nonsyndromic hearing loss 23;C1865885:Usher syndrome type 1F Pathogenic:2

Apr 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 30, 2015

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Autosomal recessive nonsyndromic hearing loss 23 Pathogenic:2

Jul 05, 2018

Laboratory of Prof. Karen Avraham, Tel Aviv University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Congenital, severe HL; observed together in digenic inheritance with NM_000260.3:c.620A>G -

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PCDH15-related disorder Pathogenic:1

Aug 19, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PCDH15 c.733C>T variant is predicted to result in premature protein termination (p.Arg245*). This variant has been reported to be causative for Usher syndrome and is one of the most common causative variants in PCDH15 in the Ashkenazi Jewish population with a frequency of 0.43% (Ben-Yosef et al. 2003. PubMed ID: 12711741; Perreault-Micale et al. 2014. PubMed ID: 25307757; Khalaileh et al. 2018. PubMed ID: 29490346; Table S2, Sharon et al. 2019. PubMed ID: 31456290). Nonsense variants in PCDH15 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Usher syndrome type 1D Pathogenic:1

Oct 18, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_033056.3(PCDH15):c.733C>T(R245*) is classified as pathogenic in the context of PCDH15-related disorders. Sources cited for classification include the following: PMID 15028842, 12711741. Classification of NM_033056.3(PCDH15):c.733C>T(R245*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -

Rare genetic deafness Pathogenic:1

Aug 27, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Arg245X variant leads to a premature stop codon at position 245, which is pr edicted to lead to a truncated or absent protein. The variant is known to be pat hogenic and is a common cause of Usher syndrome in the Ashkenazi Jewish populati on (Ben-Yosef 2003, Brownstein 2004). -

Usher syndrome type 1G Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		3.3
Vest4		0.84
GERP RS		2.5
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs111033260; hg19: chr10-56077174; COSMIC: COSV57298137;