ClinVar Miner

Submissions for variant NM_033056.4(PCDH15):c.475-3C>T (rs41304641)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000039744 SCV000063433 benign not specified 2011-04-08 criteria provided, single submitter clinical testing 475-3C>T in intron 5 of PCDH15: This variant has previously been identified as a homozygous variant in combination with another likely pathogenic PCDH15 variant in an individual with a clinical diagnosis of Usher syndrome, and therefore the 475-3C>T variant was classified as a polymorphism (http://www.umd.be/PCDH15/). This variant is also listed in dbSNP; however, frequency data is not available ( rs41304641). This variant has been identified by our laboratory in 5/224 (2%) in dividuals tested, none of whom had congenital profound hearing loss consistent w ith pathogenic variants in PCDH15. The 475-3C>T variant is located in the 5' spl ice region but does not affect the highly conserved +1 and +2 positions. In summ ary, this data suggests that this variant is likely to be benign.
Illumina Clinical Services Laboratory,Illumina RCV000345244 SCV000363244 likely benign Usher syndrome type 1 2018-01-13 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 RCV000392461 SCV000363245 uncertain significance Nonsyndromic Hearing Loss, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000948373 SCV001094578 benign not provided 2019-12-31 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000948373 SCV001144879 benign not provided 2018-11-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000039744 SCV001362474 benign not specified 2019-08-08 criteria provided, single submitter clinical testing Variant summary: PCDH15 c.475-3C>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 2/4 computational tools predict that the variant impacts normal splicing by creating a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0083 in 251012 control chromosomes in the gnomAD database, including 18 homozygotes. The observed variant frequency is approximately 2.63 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. To our knowledge, no occurrence of c.475-3C>T in individuals affected with Usher Syndrome Type 1F and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar(after 2014) and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.

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