Submissions for variant NM_001384140.1(PCDH15):c.733C>T (p.Arg245Ter)

gnomAD frequency: 0.00012  dbSNP: rs111033260

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000824735	SCV000063460	pathogenic	Rare genetic deafness	2010-08-27	criteria provided, single submitter	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).
GeneDx	RCV000269122	SCV000329455	pathogenic	not provided	2020-02-10	criteria provided, single submitter	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)
Counsyl	RCV000005218	SCV000678062	pathogenic	Usher syndrome type 1F	2015-06-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000005218	SCV000699763	pathogenic	Usher syndrome type 1F	2016-04-28	criteria provided, single submitter	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.
Fulgent Genetics, Fulgent Genetics	RCV000477806	SCV000893838	pathogenic	Autosomal recessive nonsyndromic hearing loss 23; Usher syndrome type 1D; Usher syndrome type 1F	2024-04-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000269122	SCV000938263	pathogenic	not provided	2024-10-24	criteria provided, single submitter	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.
Baylor Genetics	RCV000218809	SCV001163266	pathogenic	Usher syndrome type 1		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001030749	SCV001194009	pathogenic	Usher syndrome type 1D	2019-10-18	criteria provided, single submitter	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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000269122	SCV001480139	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000269122	SCV002016546	pathogenic	not provided	2023-01-13	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000005218	SCV003761087	pathogenic	Usher syndrome type 1F	2023-01-24	criteria provided, single submitter	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).
CeGaT Center for Human Genetics Tuebingen	RCV000269122	SCV004125399	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	PCDH15: PVS1, PM2
Baylor Genetics	RCV001004803	SCV004200763	pathogenic	Autosomal recessive nonsyndromic hearing loss 23	2024-03-27	criteria provided, single submitter	clinical testing
OMIM	RCV000005218	SCV000025396	pathogenic	Usher syndrome type 1F	2003-04-24	no assertion criteria provided	literature only
GeneReviews	RCV000055970	SCV000087017	not provided	Usher syndrome type 1G		no assertion provided	literature only
GeneReviews	RCV000218809	SCV000268758	not provided	Usher syndrome type 1		no assertion provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477806	SCV000536749	pathogenic	Autosomal recessive nonsyndromic hearing loss 23; Usher syndrome type 1D; Usher syndrome type 1F	2015-09-30	no assertion criteria provided	research
Sharon lab, Hadassah-Hebrew University Medical Center	RCV000218809	SCV001161174	pathogenic	Usher syndrome type 1	2019-06-23	no assertion criteria provided	research
Laboratory of Prof. Karen Avraham, Tel Aviv University	RCV000005218	SCV001164291	pathogenic	Usher syndrome type 1F	2018-05-07	no assertion criteria provided	research	Recessive, congenital, profound HL; USH1F
Laboratory of Prof. Karen Avraham, Tel Aviv University	RCV001004803	SCV001164292	pathogenic	Autosomal recessive nonsyndromic hearing loss 23	2018-07-05	no assertion criteria provided	research	Congenital, severe HL; observed together in digenic inheritance with NM_000260.3:c.620A>G
Natera, Inc.	RCV000005218	SCV001463335	pathogenic	Usher syndrome type 1F	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000269122	SCV001550642	pathogenic	not provided		no assertion criteria provided	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.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000269122	SCV001952749	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000269122	SCV001972547	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734497	SCV005360405	pathogenic	PCDH15-related disorder	2024-08-19	no assertion criteria provided	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.