ClinVar Miner

Submissions for variant NM_003504.5(CDC45):c.1388C>T (p.Pro463Leu)

gnomAD frequency: 0.00004  dbSNP: rs751663397
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
SIB Swiss Institute of Bioinformatics RCV000755754 SCV000883300 likely pathogenic Meier-Gorlin syndrome 7 2024-04-11 criteria provided, single submitter curation This variant is classified as likely pathogenic for Meier-Gorlin syndrome 7, based on the following evidence: this variant is found at low frequency in gnomAD (v.4) and no homozygotes are reported (PM2-supporting); it has been found in three patients, being in trans with a likely pathogenic/pathogenic variant in two of them (PMID: 27374770) (PM3-strong); all patients presented with the classical triad of Meier-Gorlin syndrome features that is short stature, microtia and absent or hypoplastic patellae (PP4); an assay in yeast indicates that the variant may affect function (PS3-supporting) (PMID: 29036220).
Revvity Omics, Revvity RCV000755754 SCV002025124 likely pathogenic Meier-Gorlin syndrome 7 2019-09-04 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002536554 SCV003444528 pathogenic not provided 2022-03-09 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CDC45 function (PMID: 29036220). 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: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 617938). This variant is also known as c.1388C>T, p.Pro463Leu. This missense change has been observed in individual(s) with Meier-Gorlin syndrome (PMID: 27374770). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs751663397, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 495 of the CDC45 protein (p.Pro495Leu).

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