Submissions for variant NM_006912.6(RIT1):c.634C>T (p.Arg212Trp)

gnomAD frequency: 0.00009  dbSNP: rs563231684

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000373670	SCV000330046	likely benign	not provided	2018-05-24	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000373670	SCV000884461	uncertain significance	not provided	2018-02-23	criteria provided, single submitter	clinical testing	The RIT1 c.634C>T; p.Arg212Trp variant (rs563231684, ClinVar variant ID 280150), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.008% (identified on 19 out of 246,228 chromosomes). The arginine at position 212 is highly conserved, considering 12 species, and computational analyses of the effects of the p.Arg212Trp variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, PolyPhen-2: benign). Based on the available information, the clinical significance of the p.Arg212Trp variant cannot be determined with certainty.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174993	SCV001338486	likely benign	not specified	2024-08-27	criteria provided, single submitter	clinical testing	Variant summary: RIT1 c.634C>T (p.Arg212Trp) results in a non-conservative amino acid change located in the Small GTPase of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251418 control chromosomes. The observed variant frequency is approximately 5.73 fold of the estimated maximal expected allele frequency for a pathogenic variant in RIT1 causing Noonan Syndrome And Related Conditions phenotype (1.3e-05). c.634C>T has not been reported in the literature in individuals affected with Noonan Syndrome And Related Conditions with clear evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 280150). Based on the evidence outlined above, the variant was classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001342293	SCV001536213	uncertain significance	Noonan syndrome 8	2025-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 212 of the RIT1 protein (p.Arg212Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RIT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 280150). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt RIT1 function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813440	SCV002060618	likely benign	Noonan syndrome and Noonan-related syndrome	2020-05-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002365291	SCV002657304	likely benign	Cardiovascular phenotype	2020-03-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.