Submissions for variant NM_002875.5(RAD51):c.877G>A (p.Ala293Thr)

dbSNP: rs1057519413

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000622620	SCV000741971	pathogenic	Inborn genetic diseases	2016-11-15	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001731668	SCV001984809	pathogenic	RAD51-related disorders	2020-08-25	criteria provided, single submitter	clinical testing	This variant has been previously reported as a de novo alteration in a patient with an atypical Fanconi Anemia who presented with growth retardation, microcephaly, hydrocephalus, skeletal (thumb and radius) abnormalities, imperforate anus and an improperly formed left testicle (NM_002875.3: c.877G>A, p.A293T; PMID: 26681308). In vitro characterization of this alteration via functional assays and biochemical studies demonstrated that the variant acts in a dominant-negative manner leading to impaired DNA binding and strand exchange activity as well as impaired ATP hydrolysis. Furthermore, patient's cells were sensitive to DNA crosslinking agents (PMID: 26681308). The c.880G>A p.Ala294Thr variant is absent from the gnomAD population database and thus is presumed to be rare. It affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.880G>A (p.Ala294Thr) variant is classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003418091	SCV004114217	likely pathogenic	RAD51-related condition	2022-09-20	criteria provided, single submitter	clinical testing	The RAD51 c.880G>A variant is predicted to result in the amino acid substitution p.Ala294Thr. This variant has been reported as arising de novo in an individual with microcephaly and intellectual disability, and described as atypical Fanconi anemia (reported as p.Ala293Thr in alternate transcript NM_002875 in Ameziane et al. 2015. PubMed ID: 26681308). Functional studies from this same report using protein expression in cultured cells indicate that the p.Ala294Thr substitution has a dominant negative effect on the wild-type protein (Ameziane et al. 2015. PubMed ID: 26681308). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Given the evidence, we interpret c.880G>A (p.Ala294Thr) as likely pathogenic.
OMIM	RCV000412566	SCV000490211	pathogenic	Fanconi anemia complementation group R	2020-06-10	no assertion criteria provided	literature only
Leiden Open Variation Database	RCV001194792	SCV001364586	uncertain significance	not provided	2014-03-15	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Najim Ameziane. Comment: Variant observed de novo.