ClinVar Miner

Submissions for variant NM_001384140.1(PCDH15):c.3717+1G>A

dbSNP: rs748706627
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169489 SCV000220943 likely pathogenic Usher syndrome type 1F 2014-12-10 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169489 SCV002051430 pathogenic Usher syndrome type 1F 2021-12-30 criteria provided, single submitter clinical testing Variant summary: PCDH15 c.3717+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250906 control chromosomes. c.3717+1G>A has been reported in the literature as compound heterozygous or homozygous genotypes in multiple comprehensively analyzed individuals affected with Usher Syndrome Type 1F (example, Le Quesne Stabej_2012, Bonnet_2016, Patel_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001850401 SCV002241017 pathogenic not provided 2022-11-01 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 189083). Disruption of this splice site has been observed in individuals with Usher syndrome (PMID: 18719945, 22135276). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 27 of the PCDH15 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PCDH15 are known to be pathogenic (PMID: 11398101, 11487575, 14570705).
Baylor Genetics RCV003474915 SCV004200832 pathogenic Autosomal recessive nonsyndromic hearing loss 23 2023-04-01 flagged submission clinical testing

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