rs111033260

chr10-54317414-G-Achr10-54317414-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_033056.4(PCDH15):c.733C>T(p.Arg245Ter) 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 (★★). 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:22 O:2
• Conservation: PhyloP100: 3.33

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-54317414-G-A is Pathogenic according to our data. Variant chr10-54317414-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54317414-G-A is described in Lovd as [Pathogenic]. Variant chr10-54317414-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_033056.4	c.733C>T	p.Arg245Ter	stop_gained	8/33	ENST00000320301.11
PCDH15	NM_001384140.1	c.733C>T	p.Arg245Ter	stop_gained	8/38	ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.733C>T	p.Arg245Ter	stop_gained	8/33	1	NM_033056.4
PCDH15	ENST00000644397.2	c.733C>T	p.Arg245Ter	stop_gained	8/38		NM_001384140.1

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

GnomAD3 exomes AF: 0.000223 AC: 56 AN: 251064 Hom.: 0 AF XY: 0.000184 AC XY: 25 AN XY: 135702

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00421

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.000397

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000290 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:22 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 13, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2020	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 01, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
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	Invitae	Jan 25, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	PCDH15: PVS1, PM2 -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Usher syndrome type 1F Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 17, 2015	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 24, 2003	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	research	Laboratory of Prof. Karen Avraham, Tel Aviv University	May 07, 2018	Recessive, congenital, profound HL; USH1F -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 28, 2016	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. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 24, 2023	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

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -

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

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 14, 2022	- -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Sep 30, 2015	- -

Autosomal recessive nonsyndromic hearing loss 23 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 30, 2023	- -
Pathogenic, no assertion criteria provided	research	Laboratory of Prof. Karen Avraham, Tel Aviv University	Jul 05, 2018	Congenital, severe HL; observed together in digenic inheritance with NM_000260.3:c.620A>G -

Usher syndrome type 1D Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Oct 18, 2019

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

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 27, 2010

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

not provided, no classification provided

literature only

GeneReviews

-

- -

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
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A;A;A;A;A
Vest4		0.84
GERP RS		2.5

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

LitVar

Other links and lift over

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