ClinVar Miner

Submissions for variant NM_033056.4(PCDH15):c.2992C>G (p.Pro998Ala) (rs397517454)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000039719 SCV000063408 uncertain significance not specified 2013-05-13 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Pro998Ala in PC DH15 has been not been reported in the literature or in large population databas es, but was identified by our laboratory in one other individual with auditory n europathy/dys-synchrony with optic atrophy. However, the variant was heterozygou s and a second PCDH15 variant was not identified. Computational analyses (bioche mical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do no t provide strong support for or against an impact to the protein. In summary, ad ditional information is needed to determined the clinical significance of this v ariant.
Counsyl RCV000671480 SCV000796456 uncertain significance Usher syndrome type 1F 2017-12-14 criteria provided, single submitter clinical testing
Invitae RCV001212794 SCV001384391 uncertain significance not provided 2019-11-05 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 998 of the PCDH15 protein (p.Pro998Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs397517454, ExAC 0.04%). This variant has not been reported in the literature in individuals with PCDH15-related conditions. ClinVar contains an entry for this variant (Variation ID: 46460). 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: "Probably 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.

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