Submissions for variant NM_005654.6(NR2F1):c.365G>A (p.Cys122Tyr)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002692671	SCV003554402	likely pathogenic	Inborn genetic diseases	2021-02-11	criteria provided, single submitter	clinical testing	The c.365G>A (p.C122Y) alteration is located in exon 1 (coding exon 1) of the NR2F1 gene. This alteration results from a G to A substitution at nucleotide position 365, causing the cysteine (C) at amino acid position 122 to be replaced by a tyrosine (Y). Based on data from the Genome Aggregation Database (gnomAD), the NR2F1 c.365G>A alteration was not observed, with coverage at this position. A missense change affecting the same amino acid, p.C122S, was reported in a patient with Bosch-Boonstra-Schaaf optic atrophy syndrome (Rech, 2020). The p.C122 amino acid is conserved in available vertebrate species. The p.C122Y alteration is located in the second C4-type Zn-finger structural domain of the DNA binding domain of NR2F1. Based on internal structural analysis, this alteration results in loss of a structurally critical Zn-binding motif in the Zn-finger domain 2 of the DNA binding domain. The p.C122Y alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
GeneDx	RCV003228126	SCV003924855	likely pathogenic	not provided	2022-11-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26986877)