Submissions for variant NM_002907.4(RECQL):c.1285A>G (p.Met429Val)

gnomAD frequency: 0.00006  dbSNP: rs368679142

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002329	SCV001160230	uncertain significance	not specified	2019-01-29	criteria provided, single submitter	clinical testing	The RECQL c.1285A>G; p.Met429Val variant (rs368679142), to our knowledge, is not reported in the medical literature or gene specific databases. This variant is found in the general population with an overall allele frequency of 0.003% (7/250844 alleles) in the Genome Aggregation Database. The methionine at codon 429 is highly conserved, but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of this variant is uncertain at this time.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001341866	SCV001535760	uncertain significance	not provided	2025-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 429 of the RECQL protein (p.Met429Val). This variant is present in population databases (rs368679142, gnomAD 0.01%). 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: 811880). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RECQL 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	RCV001341866	SCV001777723	uncertain significance	not provided	2023-08-02	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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)
Ambry Genetics	RCV001002329	SCV002695332	uncertain significance	not specified	2024-09-15	criteria provided, single submitter	clinical testing	The p.M429V variant (also known as c.1285A>G), located in coding exon 10 of the RECQL gene, results from an A to G substitution at nucleotide position 1285. The methionine at codon 429 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001341866	SCV004220197	uncertain significance	not provided	2023-01-30	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000028 (7/250844 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In a large-scale case-control study, the variant has been reported in at least one individual with breast cancer as well as in unaffected controls (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 predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.