ClinVar Miner

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

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Total submissions: 15
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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 2018-07-02 criteria provided, single submitter clinical testing The R245X variant in the PCDH15 gene has been reported previously in association with autosomal recessive type 1 Usher syndrome when present in the homozygous state in families of Ashkenazi Jewish ancestry (Ben-Yosef et al., 2003; Brownstein et al., 2004). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R245X variant is observed in 41/10142 (0.4%) alleles from individuals of Ashkenazi Jewish background, in large population cohorts, and no individuals were reported to be homozygous (Lek et al., 2016). We interpret R245X as a pathogenic variant.
Counsyl RCV000005218 SCV000678062 pathogenic Usher syndrome type 1F 2015-06-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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 2020-01-07 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.
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

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