Submissions for variant NM_002878.4(RAD51D):c.496A>G (p.Arg166Gly)

dbSNP: rs1064793246

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483552	SCV000565468	uncertain significance	not provided	2015-01-30	criteria provided, single submitter	clinical testing	This variant is denoted RAD51D c.496A>G at the cDNA level, p.Arg166Gly (R166G) at the protein level, and results in the change of an Arginine to a Glycine (AGG>GGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51D Arg166Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RAD51D Arg166Gly occurs at a position that is highly conserved across species and is located in the ATPase domain (Kim 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether RAD51D Arg166Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000541623	SCV000651754	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-05-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 166 of the RAD51D protein (p.Arg166Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RAD51D-related conditions. ClinVar contains an entry for this variant (Variation ID: 418444). 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 RAD51D 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.
Ambry Genetics	RCV002341125	SCV002644271	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-29	criteria provided, single submitter	clinical testing	The p.R166G variant (also known as c.496A>G), located in coding exon 6 of the RAD51D gene, results from an A to G substitution at nucleotide position 496. The arginine at codon 166 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.