Submissions for variant NM_002878.4(RAD51D):c.623T>C (p.Val208Ala)

dbSNP: rs1064795673

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482825	SCV000571697	uncertain significance	not provided	2016-09-18	criteria provided, single submitter	clinical testing	This variant is denoted RAD51D c.623T>C at the cDNA level, p.Val208Ala (V208A) at the protein level, and results in the change of a Valine to an Alanine (GTC>GCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51D Val208Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Valine and Alanine share similar properties, this is considered a conservative amino acid substitution. RAD51D Val208Ala occurs at a position that is 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 evidence, it is unclear whether RAD51D Val208Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000564016	SCV000671959	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-28	criteria provided, single submitter	clinical testing	The p.V208A variant (also known as c.623T>C), located in coding exon 7 of the RAD51D gene, results from a T to C substitution at nucleotide position 623. The valine at codon 208 is replaced by alanine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000649707	SCV000771539	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2020-01-31	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with RAD51D-related disease. ClinVar contains an entry for this variant (Variation ID: 422273). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with alanine at codon 208 of the RAD51D protein (p.Val208Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine.