Submissions for variant NM_006912.6(RIT1):c.244T>A (p.Phe82Ile)

dbSNP: rs869025194

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000226825	SCV000289598	pathogenic	Noonan syndrome 8	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 82 of the RIT1 protein (p.Phe82Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Noonan syndrome (PMID: 26757980; Invitae). ClinVar contains an entry for this variant (Variation ID: 183406). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt RIT1 function with a positive predictive value of 95%. This variant disrupts the p.Phe82 amino acid residue in RIT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23791108, 24939608, 25049390, 26757980). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001731491	SCV001982612	pathogenic	not provided	2021-09-28	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 26757980, 23765226)
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000226825	SCV004046201	pathogenic	Noonan syndrome 8		criteria provided, single submitter	clinical testing	This variant has been previously reported in the literature as c.244T>A (p.Phe82Ile) on the alternative transcript NM_006912.5. This variant has been previously reported as a heterozygous germline variant in one individual with Noonan Syndrome (PMID: 26757980). This variant has also been previously reported as a somatic variant in myeloid malignancies (PMID: 23765226). However, other variants affecting the same amino acid residue have been reported in ClinVar as Pathogenic variants (Variation ID: 183407, 183408, 372863, 694696, 181522, 370035). This variant is absent from the gnomAD population database and thus is presumed to be rare. The c.295T>A (p.Phe99Ile) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.295T>A (p.Phe99Ile) variant is classified as Pathogenic.
Genome-Nilou Lab	RCV000226825	SCV004050480	pathogenic	Noonan syndrome 8	2023-04-11	criteria provided, single submitter	clinical testing
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000207338	SCV000211880	pathogenic	Noonan syndrome		no assertion criteria provided	clinical testing