Submissions for variant NM_002524.5(NRAS):c.182A>C (p.Gln61Pro)

dbSNP: rs11554290

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000291285	SCV000330319	pathogenic	not provided	2016-03-22	criteria provided, single submitter	clinical testing	The Q61P variant in the NRAS gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The Q61P variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Q61P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position in codon 61 of the guanosine triphosphate-binding site that is conserved across species. The guanosine trisphophate-binding site is crucial for normal inactivation, and variants located at this site lead to constitutive activation of NRAS (Kinsler et al., 2013). Two missense variants in the same residue (Q61R, Q61K) have been reported previously as somatic alterations in association with congenital melanocytic nevi and thyroid follicular carcinomas and adenomas, supporting the functional importance of this region of the protein (Nikiforova et al., 2003; Dessars et al., 2009; Kinsler et al., 2013; Lim et al., 2014). We interpret Q61P as a pathogenic variant.
Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University	RCV003155143	SCV003844093	likely pathogenic	Noonan syndrome 6	2021-09-30	no assertion criteria provided	research