Submissions for variant NM_006912.6(RIT1):c.244T>G (p.Phe82Val)

dbSNP: rs869025194

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000263369	SCV000329958	pathogenic	not provided	2022-02-02	criteria provided, single submitter	clinical testing	Functional studies demonstrate that the F82V variant results in enhanced p-ERK levels in comparison to wild-type (Chen et al., 2014; Fang et al., 2016) and increased Elk1 transactivation (Yaoita et al., 2016); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26714497, 26757980, 32860008, 25049390, 23791108, 23765226, 24939608, 27226556, 27101134, 25959749, 27109146, 26446362, 34426522, 34008892)
Invitae	RCV000170492	SCV000659221	pathogenic	Noonan syndrome 8	2022-10-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Phe82 amino acid residue in RIT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects RIT1 function (PMID: 25049390, 26714497, 27226556). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RIT1 protein function. ClinVar contains an entry for this variant (Variation ID: 183408). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 23791108, 24939608, 25049390, 26757980, 27101134). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 82 of the RIT1 protein (p.Phe82Val).
Centogene AG - the Rare Disease Company	RCV000170492	SCV001426476	pathogenic	Noonan syndrome 8		criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000170492	SCV001976946	pathogenic	Noonan syndrome 8	2021-10-01	criteria provided, single submitter	clinical testing	PS3, PM1, PM2, PP2, PP3, PP4, PP5
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000170492	SCV001984860	pathogenic	Noonan syndrome 8	2020-05-28	criteria provided, single submitter	clinical testing	This variant is also known as c.244T>G (p.F82V) on the alternate transcript NM_006912.4 (PMID: 23791108, 25049390, 24939608, 27226556). This variant has been previously reported as a de novo heterozygous change in patients with Noonan Syndrome (NS; PMID: 23791108, 25049390, 24939608, 27848944). In one study, this alteration was identified together with a variant in the RASA2 gene (p.Y326C), and both alterations increased ERK activation in in-vitro transfection experiments (PMID: 25049390). The c.295T>G (p.Phe99Val) was also identified in a 22-year-old man with recurrent infections since childhood and suspected common variable immune deficiency (PMID: 28188499). Additionally, this variant has been identified in patients with myeloid malignancies (PMID: 27226556, 23765226). Functional characterization indicates that this variant, located in the RAS switch II domain important for GTPase activity, is a gain-of-function alteration that leads to activation of the RAS-ERK pathway by impairing GTP hydrolysis (PMID: 23791108, 27226556). It is absent from the gnomAD population database and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.295T>G (p.Phe99Val) variant on protein function. Based on the available evidence, the c.295T>G (p.Phe99Val) variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778757	SCV002015162	pathogenic	RASopathy	2021-10-03	criteria provided, single submitter	clinical testing	Variant summary: RIT1 c.244T>G (p.Phe82Val) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005525), also referred to as the Switch II domain (Cave_2016) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250842 control chromosomes. c.244T>G has been reported in the literature in multiple well phenotyped and comprehensively genotyped individuals affected with Noonan Syndrome (example, Aoki_2013, Chen_2014, Gos_2014, Cave_2016, Kouz_2016, Yaoita_2016). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in stimulation of ELK transcription (Yaoita_2016), promotes ERK activation (Chen_2014) and reduction in the rate of GTP hydrolysis (Fang_2016) consistent with a gain of function mechanism. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813420	SCV002060940	pathogenic	Noonan syndrome and Noonan-related syndrome	2017-05-10	criteria provided, single submitter	clinical testing
3billion	RCV000170492	SCV002573193	pathogenic	Noonan syndrome 8	2022-09-01	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000183408). The variant has been previously reported as de novo in a similarly affected individual (PMID: 23791108). Different missense changes at the same codon (p.Phe82Cys, p.Phe82Ile, p.Phe82Leu, p.Phe82Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000181522 , VCV000183406 , VCV000183407 , VCV000370035 , VCV000372863 , VCV000694696). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV002453562	SCV002736810	pathogenic	Cardiovascular phenotype	2020-01-06	criteria provided, single submitter	clinical testing	The p.F82V pathogenic mutation (also known as c.244T>G), located in coding exon 4 of the RIT1 gene, results from a T to G substitution at nucleotide position 244. The phenylalanine at codon 82 is replaced by valine, an amino acid with highly similar properties. This mutation was identified in multiple individuals with Noonan syndrome, including several de novo cases (Aoki Y et al. Am. J. Hum. Genet., 2013 Jul;93:173-80; Gos M et al. Am. J. Med. Genet. A, 2014 Sep;164A:2310-6; Chen PC et al. Proc. Natl. Acad. Sci. U.S.A., 2014 Aug;111:11473-8; Cavé H et al. Eur. J. Hum. Genet., 2016 08;24:1124-31; Fang Z et al. J. Biol. Chem., 2016 07;291:15641-52; Kouz K et al. Genet. Med., 2016 12;18:1226-1234). Functional studies demonstrated that this variant increased the GTP-loaded, activated state of RIT1 and impaired GTP hydrolysis (Fang Z et al. J. Biol. Chem., 2016 07;291:15641-52) and increased Elk1 transactivation compared to wild type (Yaoita M et al. Hum. Genet., 2016 Feb;135:209-22). In addition, a known disease-causing mutation, p.F82L, has been described in the same codon in individuals with Noonan syndrome (Cavé H et al. Eur. J. Hum. Genet., 2016 08;24:1124-31). Based on the supporting evidence, the p.F82V alteration is interpreted as a disease-causing mutation.
Genome-Nilou Lab	RCV000170492	SCV004050478	pathogenic	Noonan syndrome 8	2023-04-11	criteria provided, single submitter	clinical testing
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000207352	SCV000211882	pathogenic	Noonan syndrome		no assertion criteria provided	clinical testing
OMIM	RCV000170492	SCV000222924	pathogenic	Noonan syndrome 8	2014-09-01	no assertion criteria provided	literature only
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000170492	SCV001133063	likely pathogenic	Noonan syndrome 8	2019-09-26	no assertion criteria provided	clinical testing