ClinVar Miner

Submissions for variant NM_001384140.1(PCDH15):c.1306A>G (p.Thr436Ala)

gnomAD frequency: 0.00002  dbSNP: rs747795209
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001570593 SCV001794915 uncertain significance not provided 2020-08-12 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV001570593 SCV003266471 uncertain significance not provided 2022-08-16 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 436 of the PCDH15 protein (p.Thr436Ala). This variant is present in population databases (rs747795209, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PCDH15-related conditions. ClinVar contains an entry for this variant (Variation ID: 990890). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV001570593 SCV004848607 uncertain significance not provided 2021-12-13 criteria provided, single submitter clinical testing The p.Thr436Ala variant in PCDH15 has not been previously reported in individuals with hearing loss or Usher syndrome but has been identified in 0.02176% (4/18386) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 990890). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3.
Ambry Genetics RCV004035480 SCV004998813 uncertain significance Inborn genetic diseases 2023-12-18 criteria provided, single submitter clinical testing The c.1306A>G (p.T436A) alteration is located in exon 12 (coding exon 11) of the PCDH15 gene. This alteration results from a A to G substitution at nucleotide position 1306, causing the threonine (T) at amino acid position 436 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc. RCV001279004 SCV001466059 uncertain significance Usher syndrome type 1F 2020-04-10 no assertion criteria provided clinical testing

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