ClinVar Miner

Submissions for variant NM_033056.4(PCDH15):c.3983+12T>C (rs149867749)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000155382 SCV000170889 benign not specified 2013-10-17 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000155382 SCV000205069 benign not specified 2012-05-07 criteria provided, single submitter clinical testing 3983+12T>C in Intron 29 of PCDH15: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus se quence and has been identified in 0.7% (46/7020) of European American chromosome s from a broad population by the NHLBI Exome Sequencing Project (; dbSNP rs149867749).
Illumina Clinical Services Laboratory,Illumina RCV000325579 SCV000363152 likely benign Usher syndrome type 1 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000382473 SCV000363153 uncertain significance Nonsyndromic Hearing Loss, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000155382 SCV000917972 benign not specified 2018-11-16 criteria provided, single submitter clinical testing Variant summary: PCDH15 c.3983+12T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. The variant allele was found at a frequency of 0.0052 in 277196 control chromosomes in the gnomAD database, including 12 homozygotes. The observed variant frequency is approximately 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCDH15 causing Usher Syndrome Type 1F phenotype (0.0032), strongly suggesting that the variant is benign. c.3983+12T>C has been reported in the literature in individuals affected with Usher Syndrome Type 1F. These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome Type 1F. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. However, two other clinical diagnostic laboratories classified this variant as benign before 2014. Based on the evidence outlined above, the variant was classified as benign.

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