Submissions for variant NM_006270.5(RRAS):c.145T>C (p.Phe49Leu)

gnomAD frequency: 0.00107  dbSNP: rs151014532

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000632778	SCV000753964	likely benign	Noonan syndrome	2025-02-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174601	SCV001337795	likely benign	not specified	2020-01-20	criteria provided, single submitter	clinical testing	Variant summary: RRAS c.145T>C (p.Phe49Leu) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00071 in 214778 control chromosomes, predominantly at a frequency of 0.0011 within the Non-Finnish European subpopulation in the gnomAD database (exomes only), including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 440 fold of the estimated maximal expected allele frequency for a pathogenic variant in RRAS causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.145T>C has been reported in the literature in an individuals affected with Gastric Cancer without strong evidence for causality (Vogelaar_2017). This report however, does not provide unequivocal conclusions about association of the variant with Noonan Syndrome and Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV001756047	SCV002005538	likely benign	not provided	2020-07-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28875981)
CeGaT Center for Human Genetics Tuebingen	RCV001756047	SCV004140442	likely benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	RRAS: PP3, BS2
Breakthrough Genomics, Breakthrough Genomics	RCV001756047	SCV005209871	likely benign	not provided		criteria provided, single submitter	not provided
PreventionGenetics, part of Exact Sciences	RCV003905693	SCV004719145	likely benign	RRAS-related disorder	2019-08-05	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).