Submissions for variant NM_004260.4(RECQL4):c.1910T>C (p.Phe637Ser)

gnomAD frequency: 0.00003  dbSNP: rs386833848

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000801697	SCV000941489	uncertain significance	Baller-Gerold syndrome	2023-08-27	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with Rapadilino syndrome (PMID: 18716613). 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. Experimental studies have shown that this missense change affects RECQL4 function (PMID: 23238538). 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. ClinVar contains an entry for this variant (Variation ID: 56403). This variant is present in population databases (rs386833848, gnomAD 0.001%). This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 637 of the RECQL4 protein (p.Phe637Ser).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509194	SCV002819313	likely pathogenic	RECQL4-related disorder	2022-12-07	criteria provided, single submitter	clinical testing	Variant summary: RECQL4 c.1910T>C (p.Phe637Ser) results in a non-conservative amino acid change within the Helicase core (RecA-like domain 1; Jensen_2012) of the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-06 in 209680 control chromosomes. c.1910T>C has been reported in the literature in an individual affected with RAPADILINO Syndrome (Siitonen_2009), and this patient was reported as compound heterozygous with another pathogenic variant. This suggests the variant is likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, showing an elimination of helicase activity and a reduction of ATPase activity to <10% of the wild-type protein. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV003229805	SCV003927450	pathogenic	not provided	2023-04-03	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect through deficiencies in helicase and ATPase activities (Jensen et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18716613, 23238538)
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049816	SCV000082225	probable-pathogenic	Rapadilino syndrome		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV002509194	SCV004710452	uncertain significance	RECQL4-related disorder	2024-08-09	no assertion criteria provided	clinical testing	The RECQL4 c.1910T>C variant is predicted to result in the amino acid substitution p.Phe637Ser. This variant was reported in the compound heterozygous state in an individual with RAPADILINO syndrome (Siitonen et al. 2009. PubMed ID: 18716613). In vitro functional studies suggest this variant impacts protein function (Jensen et al. 2012. PubMed ID: 23238538). This variant is reported in 0.0011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.