Submissions for variant NM_002907.4(RECQL):c.1694C>T (p.Ala565Val)

dbSNP: rs1248986058

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001350670	SCV001545080	uncertain significance	not provided	2024-04-29	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 565 of the RECQL protein (p.Ala565Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RECQL-related conditions. ClinVar contains an entry for this variant (Variation ID: 1046150). 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 not expected to disrupt RECQL protein function with a negative 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	RCV001350670	SCV002000947	uncertain significance	not provided	2023-06-12	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); This variant is associated with the following publications: (PMID: 27248010, 19151156, 23396353, 30188893)
Ambry Genetics	RCV004036632	SCV002715412	uncertain significance	not specified	2024-10-14	criteria provided, single submitter	clinical testing	The p.A565V variant (also known as c.1694C>T), located in coding exon 13 of the RECQL gene, results from a C to T substitution at nucleotide position 1694. The alanine at codon 565 is replaced by valine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001350670	SCV004220208	uncertain significance	not provided	2022-10-12	criteria provided, single submitter	clinical testing	It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in a large scale breast cancer association study, the variant was observed in control individuals and not among the breast cancer cases (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/RECQL)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.