ClinVar Miner

Submissions for variant NM_001384140.1(PCDH15):c.4246C>A (p.Gln1416Lys)

gnomAD frequency: 0.00001  dbSNP: rs765215862
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001915713 SCV002187115 uncertain significance not provided 2022-08-22 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 1416 of the PCDH15 protein (p.Gln1416Lys). This variant is present in population databases (rs765215862, gnomAD 0.003%). This missense change has been observed in individual(s) with inherited retinal dystrophy (Invitae). This variant is also known as c.4261C>A (p.Gln1421Lys). ClinVar contains an entry for this variant (Variation ID: 1406208). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics RCV002484418 SCV002793777 uncertain significance Autosomal recessive nonsyndromic hearing loss 23; Usher syndrome type 1D; Usher syndrome type 1F 2021-08-12 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002555420 SCV003761037 uncertain significance Usher syndrome type 1F 2023-01-24 criteria provided, single submitter curation The p.Gln1416Lys variant in PCDH15 has been reported in 1 individual, in the compound heterozygous state, with Usher syndrome type 1F (PMID: 26969326) and has been identified in 0.003% (3/111390) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs765215862). 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. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Gln1416Lys variant is uncertain. ACMG/AMP Criteria applied: BP4, PM2_supporting (Richards 2015).

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