Submissions for variant NM_004260.4(RECQL4):c.2747C>T (p.Pro916Leu)

gnomAD frequency: 0.00014  dbSNP: rs375049839

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465330	SCV000545887	uncertain significance	Baller-Gerold syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces proline with leucine at codon 916 of the RECQL4 protein (p.Pro916Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs375049839, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with RECQL4-related conditions. ClinVar contains an entry for this variant (Variation ID: 406920). 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%. 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.
GeneDx	RCV001539644	SCV001757440	uncertain significance	not provided	2021-07-09	criteria provided, single submitter	clinical testing	Observed in individuals with cancer undergoing multi-gene panel testing (Mandelker et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33503190, 28873162, 27535533)
AiLife Diagnostics, AiLife Diagnostics	RCV001539644	SCV002501533	uncertain significance	not provided	2021-06-18	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003153601	SCV003843058	uncertain significance	Rothmund-Thomson syndrome type 2	2023-02-22	criteria provided, single submitter	clinical testing	The RECQL4 c.2747C>T (p.Pro916Leu) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In silico tools predict a benign effect of this variant on protein function, but to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with RECQL4-associated conditions. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004737511	SCV005346450	uncertain significance	RECQL4-related disorder	2024-08-05	no assertion criteria provided	clinical testing	The RECQL4 c.2747C>T variant is predicted to result in the amino acid substitution p.Pro916Leu. This variant has been reported in a patient with kidney cancer and family history of breast and kidney cancer but who also carried other variants of uncertain significance in CHEK2 and POLE (LOVD; http://www.inc.gob.ar/sither/individuals/00002309). This variant is reported in 0.092% of alleles in individuals of Ashkenazi Jewish descent in gnomAD is interpreted as a variant of uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/406920). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.