Submissions for variant NM_001384140.1(PCDH15):c.1997+1G>A

gnomAD frequency: 0.00001  dbSNP: rs763797356

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000427347	SCV000517045	pathogenic	not provided	2015-05-14	criteria provided, single submitter	clinical testing	The c.1997+1 G>A splice site variant in the PCDH15 gene destroys the canonical splice donor site inintron 16. It is also predicted to cause abnormal gene splicing, either leading to an abnormal message that issubject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used forprotein translation. The c.1997+1 G>A variant was not observed in approximately 6,500 individuals ofEuropean and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not acommon benign variant in these populations. Although this variant has not been previously reportedto our knowledge, we interpret it as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000427347	SCV000953834	pathogenic	not provided	2024-02-08	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 16 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). This variant is present in population databases (rs763797356, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with PCDH15-related conditions (PMID: 34416374, 34744965). ClinVar contains an entry for this variant (Variation ID: 379720). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000427347	SCV001447254	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307495	SCV002600591	likely pathogenic	Usher syndrome type 1F	2022-10-19	criteria provided, single submitter	clinical testing	Variant summary: PCDH15 c.1997+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 a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 250238 control chromosomes (gnomAD). c.1997+1G>A has been reported in the literature as a homozygous and compound heterozygous genotype in individuals affected with Usher Syndrome Type 1F (Wang_2021 and Guan_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1) likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002307495	SCV003761069	likely pathogenic	Usher syndrome type 1F	2023-01-24	criteria provided, single submitter	curation	The c.1997+1G>A variant in PCDH15 has been reported in 1 individual. in the compound heterozygous state, with Usher syndrome type 1F (PMID: 34416374) and has been identified in 0.005% (1/18366) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs763797356). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 379720) and has been interpreted as pathogenic or likely pathogenic by Invitae, GeneDx, and Institute of Medical Genetics and Applied Genomics (University Hospital Tübingen). This variant is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the PCDH15 gene is an established disease mechanism in autosomal recessive Usher syndrome type 1F. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive Usher syndrome type 1F. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015).
Baylor Genetics	RCV003476015	SCV004200814	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 23	2024-02-06	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004816657	SCV005070995	pathogenic	Retinal dystrophy	2018-01-01	no assertion criteria provided	clinical testing