Submissions for variant NM_033056.4(PCDH15):c.5864T>C (p.Leu1955Pro)

gnomAD frequency: 0.00001  dbSNP: rs751586980

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000408121	SCV000363096	uncertain significance	Usher syndrome type 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV002520600	SCV003511248	uncertain significance	not provided	2022-06-29	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1955 of the PCDH15 protein (p.Leu1955Pro). This variant is present in population databases (rs751586980, gnomAD 0.004%). 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: 300165). 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: "Deleterious"; PolyPhen-2: "Not Available"; 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.
Ambry Genetics	RCV003243061	SCV003950651	uncertain significance	Inborn genetic diseases	2023-03-24	criteria provided, single submitter	clinical testing	The c.5864T>C (p.L1955P) alteration is located in exon 33 (coding exon 32) of the PCDH15 gene. This alteration results from a T to C substitution at nucleotide position 5864, causing the leucine (L) at amino acid position 1955 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV002520600	SCV004036760	uncertain significance	not provided	2023-03-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge