Submissions for variant NM_004260.4(RECQL4):c.2545G>A (p.Val849Met)

gnomAD frequency: 0.00019  dbSNP: rs201661055

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000231346	SCV000288231	uncertain significance	Baller-Gerold syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 849 of the RECQL4 protein (p.Val849Met). This variant is present in population databases (rs201661055, gnomAD 0.07%). 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: 239737). 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.
Eurofins Ntd Llc (ga)	RCV000331181	SCV000332743	uncertain significance	not provided	2015-07-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818609	SCV002067060	uncertain significance	not specified	2021-07-27	criteria provided, single submitter	clinical testing	DNA sequence analysis of the RECQL4 gene demonstrated a sequence change, c.2545G>A, in exon 15 results in an amino acid change, p.Val849Met. This sequence change does not appear to have been previously described in individuals with RECQL4-related disorders and has been described in the gnomAD database with a low population frequency of 0.071% in the African subpopulation (dbSNP rs201661055). The p.Val849Met change affects a highly conserved amino acid residue located in a domain of the RECQL4 protein that is not known to be functional. The p.Val849Met substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Val849Met change remains unknown at this time.
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153533	SCV003843679	likely pathogenic	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing