ClinVar Miner

Submissions for variant NM_033056.4(PCDH15):c.733C>T (p.Arg245Ter) (rs111033260)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 Deafness, autosomal recessive 23; Usher syndrome type 1D; Usher syndrome type 1F 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000269122 SCV000938263 pathogenic not provided 2020-10-31 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. This variant is present in population databases (rs111033260, ExAC 0.04%). This variant has been observed to segregate with Usher syndrome in many families and has been reported to be a founder mutation in the Ashkenazi Jewish population (PMID: 12711741, 27460420, 22815625). ClinVar contains an entry for this variant (Variation ID: 4933). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in PCDH15 are known to be pathogenic (PMID: 11398101, 11487575, 14570705). 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 Women's Health, 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
OMIM RCV000005218 SCV000025396 pathogenic Usher syndrome type 1F 2003-04-24 no assertion criteria provided literature only
GeneReviews RCV000055970 SCV000087017 pathologic Usher syndrome, type 1G 2013-06-20 no assertion criteria provided curation Converted during submission to Pathogenic.
GeneReviews RCV000218809 SCV000268758 pathogenic Usher syndrome type 1 2016-05-19 no assertion criteria provided literature only
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477806 SCV000536749 pathogenic Deafness, autosomal recessive 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 Deafness, autosomal recessive 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.
Human Genetics - Radboudumc,Radboudumc RCV000269122 SCV001952749 pathogenic not provided no assertion criteria provided clinical testing

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