Submissions for variant NM_004260.4(RECQL4):c.1397C>T (p.Pro466Leu)

gnomAD frequency: 0.00001  dbSNP: rs386833844

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228610	SCV000288176	pathogenic	Baller-Gerold syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 466 of the RECQL4 protein (p.Pro466Leu). This variant is present in population databases (rs386833844, gnomAD 0.004%). This missense change has been observed in individual(s) with Rothmand-Thompson syndrome (RTS) (PMID: 18504617, 18716613). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56399). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RECQL4 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RECQL4 function (PMID: 23238538, 33046774). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	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
Revvity Omics, Revvity	RCV000429374	SCV002019044	likely pathogenic	not provided	2021-03-09	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.