ClinVar Miner

Submissions for variant NM_004260.3(RECQL4):c.1397C>T (p.Pro466Leu) (rs386833844)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000228610 SCV000288176 likely pathogenic Baller-Gerold syndrome 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 466 of the RECQL4 protein (p.Pro466Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs386833844, ExAC 0.01%). This variant has been reported in combination with pathogenic variants in two individuals with Rothmand-Thompson syndrome (RTS) (PMID: 18716613, 18504617). In one of these individuals, this variant was confirmed to be on the opposite chromosome of the c.1887del4 frameshift in RECQL4 (PMID: 18716613). ClinVar contains an entry for this variant (Variation ID: 56399). Experimental studies demonstrate that this missense change leads to decreased ATPase, helicase and DNA binding activity (PMID: 23238538). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000429374 SCV000332701 likely pathogenic not provided 2018-08-21 criteria provided, single submitter clinical testing
GeneDx RCV000429374 SCV000534409 likely pathogenic not provided 2018-08-17 criteria provided, single submitter clinical testing The P466L variant in the RECQL4 gene has been reported previously in one individual with Rothmund-Thomson syndrome, and in one individual with RAPADALINO syndrome; both of these individuals harbored a frameshift RECQL4 variant in trans with P466L (Jin et al., 2008; Siitonen et al., 2009). Functional studies demonstrate that the P466L variant results in decreased protein activity as compared to wild type (Jensen et al., 2012). The P466L variant is observed in 4/106770 (0.004%) alleles from individuals of non-Finnish European background, in large population cohorts (Lek et al., 2016). The P466L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret P466L as a likely pathogenic variant.
Mendelics RCV000228610 SCV001137730 likely pathogenic Baller-Gerold syndrome 2019-05-28 criteria provided, single submitter clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049812 SCV000082221 probable-pathogenic Rapadilino syndrome no assertion criteria provided not provided Converted during submission to Likely pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.