Submissions for variant NM_004959.5(NR5A1):c.938G>A (p.Arg313His)

dbSNP: rs1554721235

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521048	SCV000617598	pathogenic	not provided	2019-12-24	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that this variant results in impaired transactivation activity and structural alteration at functional domains (Perez Garrido et al., 2015); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported previously in association with severe hypospadias and variable micropenis and cryptorchidism in at least one family, affected males inherited the variant from their unaffected father (Adamovic et al., 2012); This variant is associated with the following publications: (PMID: 25160005, 23154282, 22907560, 22100173, 30425642)
Revvity Omics, Revvity	RCV000521048	SCV002020160	likely pathogenic	not provided	2021-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002527576	SCV003441482	pathogenic	Oligosynaptic infertility; 46,XY disorder of sex development	2021-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 313 of the NR5A1 protein (p.Arg313His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with NR5A1-related conditions (PMID: 22907560, 30425642). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 449434). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant disrupts the p.Arg313 amino acid residue in NR5A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22028768, 25122490, 27169744, 30425642). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University	RCV001662528	SCV001877167	pathogenic	Genetic non-acquired premature ovarian failure	2019-10-01	no assertion criteria provided	research